阅读说明：本技术 抗癌肽 (Anticancer peptides ) 是由 劳拉·内沃拉 圣地亚哥·埃斯特班·马丁 于 2018-07-31 设计创作，主要内容包括：本发明提供了一种式(I)的肽或其药用盐,以及包含该式(I)的肽或其药用盐的融合肽和药物组合物；或者,可替换地,该肽或其药用盐是氨基酸序列相对于序列SEQ ID NO：25、26、27或28具有85％至95％同一性的肽或其药用盐。本发明的肽显示出抗癌活性。<Image he="85" wi="700" file="DDA0002437331860000011.GIF" imgContent="drawing" imgFormat="GIF" orientation="portrait" inline="no"></Image>(The present invention provides a peptide of formula (I) or a pharmaceutically acceptable salt thereof, and fusion peptides and pharmaceutical compositions comprising the peptide of formula (I) or a pharmaceutically acceptable salt thereof; or, alternatively, the peptide or pharmaceutically acceptable salt thereof is a peptide having an amino acid sequence that is substantially identical to the amino acid sequence of SEQ ID NO: 25. 26, 27 or 28, or a pharmaceutically acceptable salt thereof, having from 85% to 95% identity. The peptides of the present invention show anticancer activity.)

1.A peptide consisting of formula (I):

wherein

"m", "n", "p", and "q" represent integers and are selected from 0 and 1; and is

"r" is 1 to 10;

corresponding to-C (O) R₄The C-terminus of (1);

-corresponds to-NHR₅The N-terminus of (1);

R₄is selected from-OH and-NR₁₇R₁₈A group of (a);

R₅is selected from-H and (C)₁-C₂₀) A group of alkyl groups; and

R₁₇and R₁₈Is a group independently selected from: -H and (C)₁-C₁₀) An alkyl group; or, alternatively, said peptide or pharmaceutical salt comprising the sequence of formula (I) as defined above comprises the linker diradical "L" of formula (II) "

-[(R₁)_a-(R₂)-(R₃)_b]_c-

(II)

The linker diradical "L" of formula (II) connects the alpha carbon atom of the amino acid at position "I" in the peptide sequence of formula (I) with the alpha carbon atom of the amino acid at position "I + 4" or "I + 7" in the peptide sequence of formula (I),

wherein

"a" and "b" are the same or different and are 0 or 1;

"c" is 1 to 10;

R₁and R₃Is a diradical independently selected from: (C)₁-C₁₀) An alkyl group; (C) substituted by one or more groups selected from₁-C₁₀) Alkyl groups: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；(C₂-C₁₀) An alkenyl group; (C) substituted by one or more groups selected from₂-C₁₀) Alkenyl: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；(C₂-C₁₀) An alkynyl group; and (C) substituted by one or more groups selected from₂-C₁₀) Alkynyl: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；

R₂Is a diradical selected from: -O-, C (═ O) NR₁₃、C(＝O)O、S(＝O)、S(＝O)₂、NR₁₄、(C₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl, -NR₁₅-NR₁₆-, -N ═ N-, -S-, and known ring systems comprising 3 to 14 members, said systems comprising 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from the group consisting of: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; and is

The ring system is optionally substituted with one or more groups independently selected from: halogen, -OH, -NO₂、(C₁-C₁₀) Alkyl, (C)₁-C₁₀) Haloalkyl, and (C)₁-C₁₀) alkyl-O-; and is

R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅And R₁₆Is independently selected from-H and (C)₁-C₁₀) A group of alkyl groups; and is

The amino acids connected by the linker are as shown in formula (III)

Wherein

R₁₉Is a single radical selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl groups, and known ring systems comprising 3 to 14 members, said systems comprising 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from the group consisting of: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; or, alternatively,

the peptide or pharmaceutically acceptable salt thereof is a peptide having an amino acid sequence that is substantially identical to the sequence of SEQ ID NO: 25. 26, 27 or 28, or a pharmaceutically acceptable salt thereof, having from 85% to 95% identity.

2. The peptide or pharmaceutically acceptable salt thereof according to claim 1, wherein "r", "a", "b", and "c" are 1.

3. The peptide or pharmaceutically acceptable salt thereof according to any one of the preceding claims,

R₁and R₃Is a diradical independently selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) An alkynyl group;

R₂is a diradical selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) An alkynyl group; and

R₁₉is a single radical selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) Alkynyl.

4. The peptide or pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein R is₁、R₃And R₁₉Is (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group.

5. The peptide or pharmaceutically acceptable salt thereof according to any one of the preceding claims, characterized in that "m" and "n" have the same meaning; and "p" and "q" have the same meaning.

6. The peptide or pharmaceutically acceptable salt thereof according to any one of the preceding claims, wherein the C-terminus corresponds to-C (O) OH or-C (O) NH₂And the N-terminus corresponds to-NH₂。

7. The peptide according to any of the preceding claims, characterized in that the linker diradical of formula (II) is between the alpha carbon atom of the amino acid located in position "I" in the peptide sequence of formula (I) and the alpha carbon atom of the amino acid located in position "I + 7" in the peptide sequence of formula (I), as represented by formula (Ia), formula (Ib) or formula (Ic):

Ia：

Ib：

(Ic)

wherein "m", "n", "p", "q", L, and R₁₉As defined above.

8. The peptide or pharmaceutically acceptable salt thereof according to any preceding claim, wherein the peptide or pharmaceutically acceptable salt thereof is selected from the group consisting of SEQ ID NO: 1.2, 3,4 and 7; or, alternatively, the peptide is a peptide having an amino acid sequence that is complementary to the sequence of SEQ ID NO: 1.2, 3 or 7 peptides having 85% to 95% identity.

9. The peptide of formula (I) or a pharmaceutically acceptable salt thereof according to any of the preceding claims, characterized in that it is conjugated with a label or a drug.

10. A fusion protein comprising a peptide as defined in any preceding claim and a cell penetrating peptide.

11. A pharmaceutical composition comprising a therapeutically effective amount of a peptide as defined in any one of claims 1 to 9, or a pharmaceutically acceptable salt thereof, or a fusion protein as defined in claim 10, and acceptable pharmaceutical excipients and/or carriers.

12. A peptide as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a fusion protein as defined in claim 10 for use as a medicament.

13. Use of a peptide as defined in any one of claims 1 to 9 or a pharmaceutically acceptable salt thereof or a fusion protein as defined in claim 10 or a pharmaceutical composition as defined in claim 11 for the treatment of cancer.

14. The peptide or pharmaceutically acceptable salt thereof for use according to claim 13, wherein the cancer is selected from the group consisting of: leukemia, myeloma, breast cancer, and lung cancer.

Technical Field

The present invention relates generally to the field of anti-tumor compounds, and more particularly to the design and synthesis of peptides with improved anti-cancer activity.

Background

The therapeutic use of proteins and peptides that function intracellularly is highly desirable for the treatment of cancer and other diseases.

Cancer is the result of the appearance of a variety of factors. Mutations may occur in proto-oncogenes, resulting in increased cell proliferation. Mutations may also occur in tumor suppressors that normally function to regulate cell proliferation. Mutations in DNA repair enzymes impair the ability of cells to repair damage prior to proliferation.

Tumor suppressor genes are normal genes, and deletion (loss or inactivation) of tumor suppressor genes can lead to cancer. Tumor suppressor genes encode proteins that slow cell growth and division. The wild-type allele of the tumor suppressor gene expresses a protein that inhibits abnormal cell proliferation. When a gene encoding a tumor suppressor protein is mutated or deleted, particularly if there is already an impairment in the cellular regulatory mechanisms, a complete lack of expression of the resulting mutein or tumor suppressor protein may not properly regulate cell proliferation, and abnormal cell proliferation may occur. Many well-studied human tumors and tumor cell lines have shown a deletion or non-functionality of tumor suppressor genes.

Currently, there are few effective options for treating a variety of common cancer types. The course of treatment for a given individual depends on the diagnosis, the stage to which the disease has progressed, and factors such as the age, sex, and general health of the patient. The most common cancer treatment options are surgery, radiation therapy and chemotherapy. Each of these therapies is associated with different side effects and they have different degrees of efficacy. These side effects, together with the multidrug resistance of traditional chemotherapy that has been disclosed, contribute to the urgent need for new anti-cancer drugs or treatment methods.

Anticancer peptides have become promising molecules for new anticancer agents due to their unique mechanism and some remarkable properties. However, the properties (such as specificity and sensitivity) exhibited by the peptides already disclosed in the prior art need to be further improved.

Thus, despite efforts, there remains a need to develop additional polypeptides with suitable anti-cancer properties.

Disclosure of Invention

The inventors have found that the sequence SEQ ID NO: 1 (hereinafter also referred to as "wtL 05") is active in inhibiting cancer cell proliferation. As shown below, the peptides of the present invention showed anticancer activity against several types of cancers, e.g., myeloma cells, lung cancer cells.

Accordingly, in a first aspect, the present invention provides a peptide of formula (I):

wherein

"m", "n", "p", and "q" represent integers and are selected from 0 and 1; and is

"r" is 1 to 10;

corresponding to-C (O) R₄The C-terminus of (1);

-corresponds to-NHR₅The N-terminus of (1);

R₄is selected from-OH and-NR₁₇R₁₈A group of (a);

R₅is selected from-H and (C)₁-C₂₀) A group of alkyl groups; and

R₁₇and R₁₈Is a group independently selected from: -H and (C)₁-C₁₀) An alkyl group; -; or, alternatively,

the peptide or a pharmaceutically acceptable salt thereof is a peptide having an amino acid sequence that is complementary to the sequence of SEQ ID NO: 25. 26 or 27 or a pharmaceutically acceptable salt thereof having 85% to 95% identity.

SEQ ID NO：25

SEQ ID NO：26

SEQ ID NO：27

SEQ ID NO：28

Wherein

L is a linker diradical of formula (II)

-[(R₁)_a-(R₂)-(R₃)_b]_c-

(II)

The linker diradical "L" of formula (II) connects the alpha carbon atom of the amino acid at position "I" in the peptide of formula (I) to the alpha carbon atom of the amino acid at position "I + 4" or "I + 7" in the peptide of formula (I),

"a" and "b" are the same or different and are 0 or 1;

"c" is 1 to 10;

R₁and R₃Is a diradical independently selected from: (C)₁-C₁₀) An alkyl group; (C) substituted by one or more groups selected from₁-C₁₀) Alkyl groups: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；(C₂-C₁₀) An alkenyl group; (C) substituted by one or more groups selected from₂-C₁₀) Alkenyl: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；(C₂-C₁₀) An alkynyl group; and (C) substituted by one or more groups selected from₂-C₁₀) Alkynyl: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；

R₂Is selected fromThe following diradicals: -O-, C (═ O) NR₁₃、C(＝O)O、S(＝O)、S(＝O)₂、NR₁₄、(C₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl, -NR₁₅-NR₁₆-, -N ═ N-, -S-, and known ring systems comprising 3 to 14 members, the systems comprising 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; and is

The ring system is optionally substituted with one or more groups independently selected from: halogen, -OH, -NO₂、(C₁-C₁₀) Alkyl, (C)₁-C₁₀) Haloalkyl, and (C)₁-C₁₀) alkyl-O-; and is

R₄Is selected from-OH and-NR₁₇R₁₈A group of (a);

R₅is selected from-H and (C)₁-C₂₀) A group of alkyl groups;

R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇and R₁₈Is independently selected from-H and (C)₁-C₁₀) A group of alkyl groups; and is

"X" represents an amino acid linked by a linker "L", said amino acid being represented by formula (III)

Wherein

R₁₉Is a single radical selected from: -H, (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl groups, and known ring systems comprising 3 to 14 members, the systems comprising 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-.

In a second aspect, the present invention provides a peptide of formula (XI):

wherein

"m", "n", "p", and "q" represent integers and are selected from 0 and 1; and is

"r" is 1 to 10;

the peptide optionally comprises:

linker diradicals "L" of formula (II) "

-[(R₁)_a-(R₂)-(R₃)_b]_c-

(II)

The linker diradical "L" of formula (II) connects the alpha carbon atom of the amino acid at position "I" in the peptide of formula (I) to the alpha carbon atom of the amino acid at position "I + 4" or "I + 7" in the peptide of formula (I),

corresponding to-C (O) R₄The C-terminus of (1); and

-corresponds to-NHR₅The N-terminus of (1);

wherein

"a" and "b" are the same or different and are 0 or 1;

"c" is 1 to 10;

R₁and R₃Is a diradical independently selected from: (C)₁-C₁₀) An alkyl group; is selected from one or more ofSubstituted by more than one group (C)₁-C₁₀) Alkyl groups: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；(C₂-C₁₀) An alkenyl group; (C) substituted by one or more groups selected from₂-C₁₀) Alkenyl: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；(C₂-C₁₀) An alkynyl group; and (C) substituted by one or more groups selected from₂-C₁₀) Alkynyl: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；

R₂Is a diradical selected from: -O-, C (═ O) NR₁₃、C(＝O)O、S(＝O)、S(＝O)₂、NR₁₄、(C₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl, -NR₁₅-NR₁₆-, -N ═ N-, -S-, and known ring systems comprising 3 to 14 members, the systems comprising 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; and is

The ring system is optionally substituted with one or more groups independently selected from: halogen, -OH, -NO₂、(C₁-C₁₀) Alkyl, (C)₁-C₁₀) Haloalkyl, and (C)₁-C₁₀) alkyl-O-; and is

R₄Is selected from-OH and-NR₁₇R₁₈A group of (a);

R₅is selected from-H and (C)₁-C₂₀) A group of alkyl groups;

R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅、R₁₆、R₁₇and R₁₈Is independently selected from-H and (C)₁-C₁₀) A group of alkyl groups; and is

The amino acids connected by the linker are shown as formula (III)

Wherein

R₁₉Is a single radical selected from: -H, (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl groups, and known ring systems comprising 3 to 14 members, the systems comprising 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; or, alternatively,

the peptide or a pharmaceutically acceptable salt thereof is a peptide having an amino acid sequence that is complementary to the sequence of SEQ ID NO: 17. 18, 19, 20, 21, 22, 23 or 24, or a pharmaceutically acceptable salt thereof, having 85% to 95% identity:

SEQ ID NO：17：

SEQ ID NO：18：

SEQ ID NO：19：

SEQ ID NO：20：

SEQ ID NO：21：

SEQ ID NO：22：

SEQ ID NO：23：

SEQ ID NO：24：

wherein L and X are as defined above.

In a third aspect, the present invention provides a fusion protein comprising a peptide as defined in the first or second aspect of the invention.

In a fourth aspect, the present invention provides a pharmaceutical composition comprising a therapeutically effective amount of a peptide of the invention or a pharmaceutically acceptable salt thereof as defined in the first or second aspect of the invention, or a fusion protein as defined in the second aspect of the invention, and an acceptable pharmaceutical excipient and/or carrier.

In a fifth aspect, the present invention provides a peptide as defined in the first or second aspect of the invention or a pharmaceutically acceptable salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, for use as a medicament. This aspect may alternatively be expressed as the use of a peptide as defined in the first or second aspect of the invention, or a pharmaceutically acceptable salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention, in the manufacture of a medicament for the treatment of a disease. This aspect may alternatively be expressed as a method for the treatment of a disease, the method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide as defined in the first or second aspect of the invention or a pharmaceutically acceptable salt thereof or a fusion protein of the third aspect of the invention or a pharmaceutical composition of the fourth aspect of the invention.

In a sixth aspect, the present invention provides a peptide as defined in the first or second aspect of the invention or a pharmaceutically acceptable salt thereof, or a fusion protein as defined in the third aspect of the invention or a pharmaceutical composition as defined in the fourth aspect of the invention for use in the treatment of cancer. This aspect may alternatively be expressed as the use of a peptide as defined in the first or second aspect of the invention or a pharmaceutically acceptable salt thereof or a fusion protein as defined in the third aspect of the invention or a pharmaceutical composition as defined in the fourth aspect of the invention in the manufacture of a medicament for the treatment of cancer. This aspect may alternatively be expressed as a method for the treatment of cancer, the method comprising administering to a subject in need thereof a therapeutically effective amount of a peptide as defined in the first or second aspect of the invention or a pharmaceutically acceptable salt thereof or a fusion protein as defined in the third aspect of the invention or a pharmaceutical composition as defined in the fourth aspect of the invention.

In other aspects, the invention provides: (a) a combination comprising a peptide as defined in the first or second aspect of the invention, or a pharmaceutically acceptable salt thereof, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention; and a therapeutic agent, in particular an anticancer agent; (b) a combination comprising a peptide as defined in the first or second aspect of the invention, or a pharmaceutically acceptable salt thereof, or a fusion protein of the third aspect of the invention, or a pharmaceutical composition of the fourth aspect of the invention; and a therapeutic agent, in particular an anticancer agent, for use as a medicament, more particularly for the treatment of cancer; (c) a peptide or a pharmaceutically acceptable salt thereof as defined in the first or second aspect of the invention, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention, for use in a combination therapy for the prevention or treatment of cancer, wherein the therapy comprises simultaneous, sequential or separate administration to a subject of an anti-cancer agent; and (d) an anti-cancer agent for use in combination therapy with a peptide or a pharmaceutically acceptable salt thereof as defined in the first or second aspect of the invention, or a fusion protein as defined in the third aspect of the invention, or a pharmaceutical composition as defined in the fourth aspect of the invention, wherein the use comprises the prevention or treatment of cancer.

Detailed Description

Unless otherwise indicated, all terms used herein should be understood in their ordinary meaning as known in the art. Other more specific definitions for certain terms as used in this application are set forth below and are intended to apply uniformly throughout the specification and claims, unless an otherwise expressly set out definition provides a broader definition.

For the purposes of the present invention, any range given includes the lower and upper endpoints of that range.

The present invention provides a peptide comprising a sequence of formula (I) as described above.

As used herein, the term "pharmaceutically acceptable salt" refers to those salts which are, within the scope of sound medical judgment, suitable for use in contact with the tissues of humans and lower animals without excessive toxicity, irritation, allergic response, and the like, and are commensurate with a reasonable benefit/risk ratio. Pharmaceutically acceptable salts are well known in the art. Examples of pharmaceutically acceptable, non-toxic acid addition salts are amino salts formed with inorganic acids (e.g., hydrochloric acid, hydrobromic acid, phosphoric acid, sulfuric acid, and perchloric acid) or with organic acids (e.g., acetic acid, trifluoroacetic acid, oxalic acid, maleic acid, tartaric acid, citric acid, succinic acid, or malonic acid) or by using other methods used in the art (e.g., ion exchange). Other pharmaceutically acceptable salts include adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecylsulfate, ethanesulfonate, formate, fumarate, glucoheptonate, glycerophosphate, gluconate, hemisulfate, heptanoate, hexanoate, hydroiodide, 2-hydroxy-ethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectate, persulfate, 3-phenylpropionate, phosphate, tartrate, dihydrofolate, and pharmaceutically acceptable salts thereof, Picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, p-toluenesulfonate, undecanoate, valerate and the like. Salts derived from suitable bases include alkali metals, alkaline earth metals, and ammonium. Representative alkali or alkaline earth metal salts include sodium, lithium, potassium, calcium, magnesium, and the like. Other pharmaceutically acceptable salts include, where appropriate, non-toxic ammonium, quaternary ammonium and amine cations formed using counterions such as halides, hydroxides, carboxylates, sulfates, phosphates, nitrates, lower alkyl sulfonates and aryl sulfonates.

In one embodiment of the first aspect of the invention, the peptide is one wherein r is 1 to 3. In another embodiment of the first aspect of the invention, the peptide is a peptide wherein r is 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide is a peptide wherein m and n are the same. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, m and n are 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide is a peptide wherein p and q are the same. In another embodiment of the first aspect of the invention, the peptide is wherein p and q are 0. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide is a peptide wherein r is 1, m and n are 1, and p and q are 0. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide is as set forth in the sequence SEQ id no: 1 (hereinafter also referred to as "wtL 05"):

Arg-Lys-Arg-Arg-Asn-Asp-Leu-Arg-Ser-Arg-Phe-Leu-Ala-Leu-Arg-Asp-Gln

surprisingly, when the sequence SEQ ID NO: 1, the peptide sequence becomes significantly active in inhibiting cancer cell proliferation in other non-related cancer cell lines (see table 2 below). The peptides of the invention show efficiencies such that a small amount is required to achieve the desired effect.

Thus, in one embodiment of the first aspect of the invention, the peptide of formula (I) or a pharmaceutically acceptable salt thereof comprises a linker diradical of formula (II)

-[(R₁)_a-(R₂)-(R₃)_b]_c-

(II)

The linker diradical of formula (II) connects the alpha carbon atom of the amino acid at position "I" in the peptide of formula (I) to the alpha carbon atom of the amino acid at position "I + 4" or "I + 7" in the peptide of formula (I),

wherein

"a" and "b" are the same or different and are 0 or 1;

"c" is 1 to 10;

R₁and R₃Is a diradical independently selected from: (C)₁-C₁₀) An alkyl group; (C) substituted by one or more groups selected from₁-C₁₀) Alkyl groups: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；(C₂-C₁₀) An alkenyl group; (C) substituted by one or more groups selected from₂-C₁₀) Alkenyl: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；(C₂-C₁₀) An alkynyl group; and (C) substituted by one or more groups selected from₂-C₁₀) Alkynyl: halogen, (C)₁-C₁₀) Alkyl, -OR₆、-NR₇R₈、-SR₉、-SOR₁₀、-SO₂R₁₁and-CO₂R₁₂；

R₂Is a diradical selected from: -O-, C (═ O) NR₁₃、C(＝O)O、S(＝O)、S(＝O)₂、NR₁₄、(C₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl, -NR₁₅-NR₁₆-, -N ═ N-, -S-, and known ring systems comprising 3 to 14 members, the systems comprising 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; and is

The ring system is optionally substituted with one or more groups independently selected from: halogen, -OH, -NO₂、(C₁-C₁₀) Alkyl, (C)₁-C₁₀) Haloalkyl, and (C)₁-C₁₀) alkyl-O-; and is

R₆、R₇、R₈、R₉、R₁₀、R₁₁、R₁₂、R₁₃、R₁₄、R₁₅And R₁₆Is independently selected from-H and (C)₁-C₁₀) A group of alkyl groups; and the amino acids connected by the linker are shown as formula (III)

Wherein

R₁₉Is a single radical selected from: -H, (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl groups, and known ring systems comprising 3 to 14 members, the systems comprising 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O.

Term (C)₁-C₁₀) Alkyl refers to a saturated straight or branched alkyl chain having 1 to 10 carbon atoms. Illustrative non-limiting examples are: methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, n-pentyl, neopentyl and n-hexyl.

Term (C)₁-C₂₀) Alkyl refers to a saturated straight or branched alkyl chain having 1 to 20 carbon atoms.

Term (C)₂-C₂₀) Alkenyl refers to a saturated straight or branched alkyl chain containing 2 to 10 carbon atoms and also containing one or more double bonds. Illustrative non-limiting examples are ethenyl, propenyl, butenyl, 1-methyl-2-buten-1-yl, and the like.

Term (C)₂-C₂₀) Alkynyl means a saturated, straight-chain or branched alkyl group containing from 2 to 20 carbon atoms and also containing one or more triple bondsAnd (3) a chain. Among them, examples include ethynyl, 1-propynyl, 2-butynyl, 1, 3-butadienyl, 4-pentynyl, and 1-hexynyl.

The term "halogen" refers to a group consisting of five chemically related elements of the periodic table: fluorine (F), chlorine (Cl), bromine (Br), iodine (I), and astatine (At).

Term (C)₁-C₁₀) Haloalkyl means substituted by one or more, preferably 1 to 6, halogen atoms which may be the same or different (C)₁-C₁₀) A group derived from one or more hydrogen atoms in an alkyl group. Among them, examples include trifluoromethyl, fluoromethyl, 1-chloroethyl, 2-chloroethyl, 1-fluoroethyl, 2-bromoethyl, 2-iodoethyl, 2,2, 2-trifluoroethyl, pentafluoroethyl, 3-fluoropropyl, 3-chloropropyl, 2,2,3, 3-tetrafluoropropyl, 2,2,3,3, 3-pentafluoropropyl, heptafluoropropyl, 4-fluorobutyl, and nonafluorobutyl.

As used herein, the term "known" ring system refers to ring systems that are chemically feasible and known in the art, and is therefore intended to exclude those that are not chemically feasible.

According to the invention, when a ring system is formed by "split" rings, it is meant that the ring system is formed by two, three or four rings, and that the rings are bonded from an atom of one ring to an atom of the other ring via a bond. The term "isolated" also includes embodiments in which the ring system has only one ring. Illustrative, non-limiting examples of known ring systems consisting of one ring are those derived from: cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl, cycloheptyl, cyclopropenyl, cyclobutenyl, cyclopentenyl, phenyl, and cycloheptenyl.

According to the invention, when the ring system has "fully fused" rings, it is meant that the ring system is formed by two, three or four rings, wherein two adjacent rings share two or more atoms. Illustrative non-limiting examples are 1,2,3, 4-tetrahydronaphthyl, 1-naphthyl, 2-naphthyl, anthryl, or phenanthryl.

According to the present invention, when a ring system is "partially fused" it means that the ring system is formed of three or four rings, at least two of the rings being fully fused (i.e. two adjacent rings share two or more atoms) and the remaining rings being bonded via a bond from an atom of one ring to an atom of one of the fused rings.

Unless otherwise indicated, the amino acids forming the peptides of the invention may have either the L-configuration or the D-configuration.

The amino acids used to construct the peptides of the invention may be prepared by organic synthesis or obtained by other routes, such as, for example, degradation of or isolation from natural sources.

In an embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided below, r is 1 to 3. In an embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided below, r ═ 1. The peptide of the first aspect of the invention therefore consists of an amino acid sequence of formula (I).

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and a ═ 1. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and b ═ 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and c ═ 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and a ═ b ═ c ═ 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and a ═ b ═ c ═ r ═ 1.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₁And R₃Is a diradical independently selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) Alkynyl. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₂Is a diradical selected from: -O-, C (═ O) NR₁₃、C(＝O)O、S(＝O)、S(＝O)₂、NR₁₄、(C₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl, -NR₁₅-NR₁₆-, -N ═ N-, -S-, and known ring systems consisting of a ring of 3 to 6 members:

is saturated, partially unsaturated, or aromatic;

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; and is

The ring system is optionally substituted with one or more groups independently selected from: halogen, -OH, -NO₂、(C₁-C₁₀) Alkyl, (C)₁-C₁₀) Haloalkyl, and (C)₁-C₁₀) alkyl-O-.

In another aspect of the present inventionIn one embodiment, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₂Is a diradical selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) Alkynyl. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₂Is (C)₂-C₁₀) An alkenyl group.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R₂Is (C)₂-C₁₀) An alkenyl group.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group; r₂Is (C)₂-C₁₀) An alkenyl group; and a, b, c, 1.

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group; r₂Is (C)₂-C₁₀) An alkenyl group; and r, a, b, c, 1.

In another embodiment of the first aspect of the invention, optionally together with the above or below mentionedIn combination with any of the embodiments, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₁₉Selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) Alkynyl. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₁₉Is (C)₁-C₁₀) Alkyl mono-radical. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (I), comprising an "L" linker between two X amino acids, and R₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R₂Is (C)₂-C₁₀) An alkenyl group.

In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, R₄is-OH (i.e., C-terminal-C (O) OH). In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, R₄is-NR₁₇R₁₈，R₁₇And R₁₈Have the same meaning. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, R₄is-NH₂(i.e., C-terminal-C (O) NH)₂)。

In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the N-terminus corresponds to-NH₂. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the C-terminus and N-terminus of the peptide of the invention are-C (o) OH and-NH, respectively₂. In another embodiment of the first aspect of the invention, optionally with above or belowIn combination with any of the embodiments provided, the C-terminus and N-terminus of the peptide of the invention are-C (O) NH, respectively₂and-NH₂。

In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, "m" and "n" are the same (i.e., both 0 or 1).

In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, "p" and "q" are the same (i.e., both 0 or 1).

In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, "m" and "n" are 1, and "p" and "q" are 0.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the linker diradical of formula (II) is between the alpha carbon atom of the amino acid located at position "I" in the peptide sequence of formula (I) and the alpha carbon atom of the amino acid located at position "I + 7" in the peptide sequence of formula (I).

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide of formula (I) or a pharmaceutically acceptable salt thereof is one of formula (Ia), formula (Ib) or formula (Ic):

Ia：

Ib：

(Ic)：

wherein "m", "n", "p", "q", L, and R₁₉As defined aboveAnd (5) defining.

In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia). In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia), wherein "m" and "n" are the same. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia), wherein "m" and "n" are 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia), wherein "p" and "q" are the same. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia), wherein "p" and "q" are 0. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia) wherein "m" and "n" are 1, "p" and "q" are 0, R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia) wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Is a phaseAre the same or different and represent (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia) wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ib). In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ib), wherein "m" and "n" are the same. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia), wherein "m" and "n" are 1. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ib), wherein "p" and "q" are the same. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ia), wherein "p" and "q" are 0. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ib), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally withAny of the embodiments provided above or below in combination, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ib), wherein "m" and "n" are 1, "p" and "q" are 0, R₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ib) wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ib) wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In one embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic). In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic), wherein "m" and "n" are the same. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic), wherein "m" and "n" are 0. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic), wherein "p" and "q" are the same. In bookIn another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic), wherein "p" and "q" are 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic) wherein "m" and "n" are 0, "p" and "q" are 1, and R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic) wherein "m" and "n" are 0, "p" and "q" are 1, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ic) wherein "m" and "n" are 0, "p" and "q" are 1, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In another embodiment of the first aspect of the invention, the peptide is selected from the group consisting of the sequences SEQ ID NO: 2. 3,4 and 7:

SEQ ID NO: 2 (hereinafter also referred to as "LS 05")

SEQ ID NO: 3 (hereinafter also referred to as "LS 13")

SEQ ID NO: 4 (hereinafter also referred to as "LS 15")

SEQ ID NO: 7 (hereinafter also referred to as "La 05")

In an alternative embodiment of the first aspect of the invention, the peptide or pharmaceutically acceptable salt thereof is a peptide having the sequence of SEQ id no: 25-28 is a peptide having from 85% to 95% identity. In another embodiment of the first aspect of the invention, the peptide or pharmaceutically acceptable salt thereof is a peptide having the sequence of SEQ ID NO: 25-28, and L and X are as defined in any of the embodiments above. In another alternative embodiment of the first aspect of the invention, the peptide has a sequence relative to the sequence SEQ ID NO: 25-28 has 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% identity; "L" is a linker diradical in which "m" and "n" are 1, "p" and "q" are 0, R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl as defined in any of the embodiments above; and "X" is an amino acid residue, wherein R₁₉Is represented by (C)₁-C₁₀) An alkyl group. In another alternative embodiment, the amino acid sequence of the peptide is identical to the amino acid sequence of SEQ ID NO: 2. 3,4 or 7 has 85% to 95% identity. In another alternative embodiment of the first aspect of the invention, the peptide has a sequence relative to the sequence SEQ ID NO: 2. 3,4 or 7 have 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95% identity.

In the present invention, the term "identity" refers to the percentage of residues or bases in two sequences that are identical when optimally aligned. A sequence exhibits identity with respect to a position in the first sequence if that position is occupied by the same amino acid residue or nucleotide as the corresponding position in the second sequence in the optimal alignment. The level of identity (or "percent sequence identity") between two sequences is measured in terms of the ratio of the number of identical positions common to the sequences relative to the size of the sequences (i.e., percent sequence identity ═ number of identical positions/total number of positions) × 100). In one embodiment, when calculating the relative position of SEQ ID NO: 2. 3,4 or 7, or 25-28, and the alignment is performed to determine the same position, without regard to the two amino acid residues linked by the linker.

Many mathematical algorithms for rapidly obtaining optimal alignments and calculating identity between two or more sequences are known and incorporated into many available software programs. Examples of such programs include MATCH-BOX, MULTIIN, GCG, FASTA and ROBUST programs, among others, for amino acid sequence analysis. Preferred software analysis programs include ALIGN, CLUSTAL W, and BLAST programs (e.g., BLAST 2.1, BL2SEQ and subsequent versions thereof).

For amino acid sequence analysis, weight matrices, such as BLOSUM matrices (e.g., BLOSUM45, BLOSUM50, BLOSUM62, and BLOSUM80 matrices), Gonnet matrices, or PAM matrices (e.g., PAM30, PAM70, PAM120, PAM160, PAM250, and PAM350 matrices) are used to determine identity.

The BLAST program provides for the analysis of at least two amino acid sequences either by aligning a selected sequence with a plurality of sequences in a database (e.g., GenSeq) or between two selected sequences using the BL2 SEQ. The BLAST program is preferably modified by a low complexity filter program, such as the DUST program or the SEG program, which is preferably integrated into the BLAST program operation. If a gap existence penalty (or gap score) is used, the gap existence penalty is preferably set between about-5 and-15. Similar slot parameters may be used with other programs as appropriate. For example, Altschul et al, "Basic local alignment search tool", 1990, J.Mol.biol, v.215, pages 403-.

For multiple sequence analysis, the CLUSTAL W program can be used. Ideally, the CLUSTAL W program is run using "dynamic" (as opposed to "fast") settings. Amino acid sequences are evaluated based on the level of identity between sequences using a set of variable BLOSUM matrices. For example, the CLUSTAL W program and its underlying principles are further described by Higgins et al, "CLUSTAL V: amplified software for multiplex alignment", 1992, CABIOS,8(2), pages 189 and 191.

In a second aspect, the present invention provides a peptide of formula (XI), or a pharmaceutically acceptable salt thereof, optionally comprising an "L" linker between two "X" amino acids, wherein "L" and "X" are as defined above.

In one embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided below, r is 1 to 3. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided below, r ═ 1. The peptide of the second aspect of the invention therefore consists of an amino acid sequence of formula (XIbis):

(Ser)m-Lys)n-Ala-Pro-Lys-Val-Val-lle-Leu-Ser-Lys-Ala-Leu-Glu-Tyr-Leu-Gln)p-(Ala)q

wherein m, n, p, and q are as defined above.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided below, the peptide or pharmaceutically acceptable salt thereof consists of an amino acid sequence of formula (XIbis), wherein m and n are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof consists of an amino acid sequence of formula (XIbis), wherein m and n are 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof consists of an amino acid sequence of formula (XIbis), wherein p and q are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof consists of an amino acid sequence of formula (XIbis), wherein p and q are 1. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide of formula (XIbis) is as set forth in sequence SEQ ID NO: 16 is as follows:

Ser-Lys-Ala-Pro-Lys-Val-Val-lle-Leu-Ser-Lys-Ala-Leu-Glu-Tyr-Leu-Gln-Ala

in another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI) and comprises an "L" linker between two X amino acids. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and a ═ 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and b ═ 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and c ═ 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and a ═ b ═ c ═ 1. In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and a ═ b ═ c ═ r ═ 1.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₁And R₃Is a diradical independently selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) Alkynyl. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₂Is a diradical selected from: -O-, C (═ O) NR₁₃、C(＝O)O、S(＝O)、S(＝O)₂、NR₁₄、(C₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, (C)₂-C₁₀) Alkynyl, -NR₁₅-NR₁₆-, -N ═ N-, -S-, and known ring systems consisting of a 3 to 6-member ring:

is saturated, partially unsaturated, or aromatic;

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; and is

The ring system is optionally independently selected from one or more ofSubstitution of each group: halogen, -OH, -NO₂、(C₁-C₁₀) Alkyl, (C)₁-C₁₀) Haloalkyl, and (C)₁-C₁₀) alkyl-O-.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₂Is a diradical selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) Alkynyl. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₂Is (C)₂-C₁₀) An alkenyl group.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group; r₂Is (C)₂-C₁₀) An alkenyl group; and a, b, c, 1.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₁And R₃Are the same or differentAnd represents (C)₁-C₁₀) An alkyl group; r₂Is (C)₂-C₁₀) An alkenyl group; and r, a, b, c, 1.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₁₉Selected from: (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl and (C)₂-C₁₀) Alkynyl. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₁₉Is (C)₁-C₁₀) Alkyl mono-radical. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XI), comprising an "L" linker between two X amino acids, and R₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, R₄is-OH (i.e., C-terminal-C (O) OH). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, R₄is-NR₁₇R₁₈，R₁₇And R₁₈Have the same meaning. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, R₄is-NH₂(i.e., C-terminal-C (O) NH)₂)。

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the N-terminus corresponds to-NH₂. In the first aspect of the inventionIn another embodiment of the second aspect, optionally in combination with any of the embodiments provided above or below, the C-terminus and N-terminus of the peptide of the invention are-C (O) OH and-NH, respectively₂. In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, the C-terminus and N-terminus of the peptide of the invention are-C (o) NH, respectively₂and-NH₂。

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, "m" and "n" are the same (i.e., both 0 or 1).

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, "p" and "q" are the same (i.e., both 0 or 1).

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, "m" and "n" are 1, and "p" and "q" are 0.

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the linker diradical of formula (II) is between the alpha carbon atom of the amino acid located at position "I" in the peptide sequence of formula (I) and the alpha carbon atom of the amino acid located at position "I + 7" in the peptide sequence of formula (I).

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide of formula (XI), or a pharmaceutically acceptable salt thereof, is one of formula (XIa), formula (XIb), formula (XIc), formula (XId), formula (XIe), formula (XIf), formula (XIg), and formula (XIh):

XIa：

XIb：

XIc：

XId：

XIe：

XIf：

XIg：

XIh：

wherein "m", "n", "p", "q", L, R₅And R₁₉As hereinbefore defined in the second aspect of the invention or any embodiment of the second aspect of the invention.

In one embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa), wherein "m" and "n" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa), wherein "m" is"and" n "are 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa), wherein "p" and "q" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa), wherein "p" and "q" are 0. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa), wherein "m" and "n" are 1, "p" and "q" are 0, R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIa), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIb). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIb), wherein "m" and "n" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIb), wherein "p" and "q" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIb), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (Ib) wherein "m" and "n" are 1, "p" and "q" are 0, R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIb), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIb), wherein "m" and "n" are 1 and "p" and "q"Is 0, a, b, c, 1, R₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In one embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc), wherein "m" and "n" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc), wherein "m" and "n" are 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc), wherein "p" and "q" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc), wherein "p" and "q" are 0. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc) wherein "m" and "n" are 1, "p" and "q" are 0, R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In the present inventionIn another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIc), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In one embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XId). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XId), wherein "m" and "n" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XId), wherein "m" and "n" are 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XId), wherein "p" and "q" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XId), wherein "p" and "q" are 0. In another embodiment of the second aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereofIs one of the formula (XId), wherein R₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XId), wherein "m" and "n" are 1, "p" and "q" are 0, R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XId), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XId), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In one embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe), wherein "m" and "n" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or belowAnd the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe), wherein "m" and "n" are 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe), wherein "p" and "q" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe), wherein "p" and "q" are 0. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe), wherein "m" and "n" are 1, "p" and "q" are 0, and R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIe), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In one embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf), wherein "m" and "n" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf), wherein "m" and "n" are 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf), wherein "p" and "q" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf), wherein "p" and "q" are 0. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf), wherein "m" and "n" are 1, "p" and "q" are 0, and R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf), wherein "m "and" n "are 1," p "and" q "are 0, a ═ b ═ c ═ 1, R₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIf), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In one embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg), wherein "m" and "n" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg), wherein "m" and "n" are 1. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg), wherein "p" and "q" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg), wherein "p" and "q" are 0. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg), wherein "m" and "n" are 1, "p" and "q" are 0, and R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIg), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In one embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIh). In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIh), wherein "m" and "n" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIh), wherein "m" and "n" are 1. In another embodiment of the second aspect of the invention, optionally with above or belowIn combination with any of the embodiments provided, the peptide, or a pharmaceutically acceptable salt thereof, is one of formula (XIh), wherein "p" and "q" are the same. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIh), wherein "p" and "q" are 0. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIh), wherein R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIh), wherein "m" and "n" are 1, "p" and "q" are 0, and R is₁、R₃And R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the second aspect of the present invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIh), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) An alkenyl group. In another embodiment of the first aspect of the invention, optionally in combination with any of the embodiments provided above or below, the peptide or pharmaceutically acceptable salt thereof is one of formula (XIh), wherein "m" and "n" are 1, "p" and "q" are 0, a ═ b ═ c ═ 1, R ═ b ═ c ═ 1, and₁、R₃and R₁₉Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl, C-terminal selected from-C (O) OH and-CONH₂And the N-terminus is-NH₂。

In another embodiment of the second aspect of the invention, the peptide is as set forth in sequence SEQ ID NO: 5. 6, 10, 11, 12, 13, 14 or 15:

SEQ ID NO: 5 (hereinafter also referred to as "LS 16")

SEQ ID NO: 6 (hereinafter also referred to as "LS 17")

SEQ ID NO: 10 (hereinafter also referred to as "Lb 01")

SEQ ID NO: 11 (hereinafter also referred to as "Lb 02")

SEQ ID NO: 12 (hereinafter also referred to as "Lb 03")

SEQ ID NO: 13 (hereinafter also referred to as "Lb 04")

SEQ ID NO: 14 (hereinafter also referred to as "Lb 05")

SEQ ID NO: 15 (hereinafter also referred to as "Lb 06")

In an alternative embodiment of the second aspect of the invention, the peptide or pharmaceutically acceptable salt thereof is a peptide having an amino acid sequence which is substantially identical to the amino acid sequence of SEQ ID NO: 17. a peptide having 85% to 95% identity to any of sequences 18, 19, 20, 21, 22, 23 or 24. In another embodiment of the first aspect of the invention, the peptide or pharmaceutically acceptable salt thereof is a peptide having the sequence of SEQ ID NO: 17-24, and L and X are as defined in any of the embodiments above, with 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, 95%, 96%, 97%, 98%, 99% sequence identity. In another alternative embodiment of the first aspect of the invention, the peptide has a sequence relative to the sequence SEQ ID NO: 17-24 has 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94%, or 95% identity; "L" is a linker diradical in which "m" and "n" are 1, "p" and "q" are 0, R₁And R₃Are identical or different and denote (C)₁-C₁₀) An alkyl group; and R is₂Is (C)₂-C₁₀) Alkenyl as defined in any of the embodiments above; and "X" is an amino acid residue, wherein R₁₉Is represented by (C)₁-C₁₀) An alkyl group. In another alternative embodiment, the amino acid sequence of the peptide is identical to the amino acid sequence of SEQ ID NO: 5-6, 10-15 has 85% to 95% identity. In another alternative embodiment of the first aspect of the invention, the peptide has a sequence relative to the sequence SEQ ID NO: 5-6 or 10-15 has 85%, 86%, 87%, 88%, 89%, 90%, 91%, 92%, 93%, 94% or 95% identity.

In one embodiment, the sequence when compared to the sequence SEQ ID NO: 5-6, 10-15, 17, 18, 19, 20, 21, 22, 23, or 24, when calculating identity, the two amino acid residues (X amino acids) joined by a linker are not considered when aligning to determine the same position.

In one embodiment, the peptide of the first or second aspect of the invention is conjugated to a label. In one embodiment, the label is conjugated to the N-terminus of the peptide.

As used herein, a "label" is a molecule or compound that can be detected by a variety of methods including fluorescence, conductivity, radioactivity, size, and the like. The label itself may be capable of emitting a signal, such as a fluorescent label that emits light of a particular wavelength after being excited by light of another, lower characteristic wavelength. Alternatively, the label may not be able to signal itself, but it may be able to bind to another compound that signals. An example of the latter is a label such as biotin, which does not emit a signal by itself but can be detected when bound to a labeled avidin or streptavidin molecule. Other examples of this latter label are ligands that specifically bind to a particular receptor. The detectably labeled receptor is bound to a ligand-labeled unit-specific marker in order to visualize such marker.

Labels that may be used in accordance with the present invention include, but are not limited to, electron spin resonance molecules, fluorescent molecules, chemiluminescent molecules, radioisotopes, enzyme substrates, enzymes, biotin molecules, avidin molecules, charge transfer molecules, semiconductor nanocrystals, semiconductor nanoparticles, colloidal gold nanocrystals, ligands, microbeads, magnetic beads, paramagnetic molecules, quantum dots, chromogenic substrates, affinity molecules, proteins, peptides, nucleic acids, carbohydrates, haptens, antigens, antibodies, antibody fragments, and lipids.

Radioisotopes can be detected with a membrane or Charge Coupled Device (CCD), ligands can be detected by binding to a receptor with a fluorescent, chemiluminescent, or enzyme label, and microbeads can be detected using electron or atomic force microscopy.

Conjugation of the label to the peptide may be carried out according to conventional protocols well known to those skilled in the art.

In another embodiment, the peptide of the first or second aspect of the invention is conjugated to a drug. In one embodiment, the drug is conjugated to the N-terminus of the peptide.

The method for preparing a peptide according to the first or second aspect of the invention comprises:

(1.a) coupling the corresponding amino acids of the peptide by condensation with a compound of formula (IV) and a compound of formula (V) corresponding to the amino acids referred to as "i" and "i + 4" or "i + 7". Compounds (IV) and (V) will be those which undergo a subsequent cyclisation step to generate the "L" diradical:

wherein R is₁₉As defined above, Z₁And Z₂Are identical or different and denote (C)₂-C₁₀) An alkenyl group; and

(1.b) performing a cyclisation step in a solution containing a Grubbs (generation I or II) catalyst, the cyclisation step comprising Z₁And Z₂Ring-Closing Metathesis (Ring-Closing Metathesis) (see Kim Young-Woo et al, "" Synthesis all-hydrocarbon staged a-fatty Peptides by Ring-Closing Metathesis ", Nature Protocols,2011,6(6), p.761-771; Scott J.M.et al," "Application of Ring-Closing Metathesis to the Synthesis of Ring-Closing Aminoacids and Peptides", J.Am.Chem.Soc.,1996, v.118(40), pp 9606-; or, alternatively,

(2a) coupling of the desired amino acids by condensation includes compounds of formula (VI) and compounds of formula (VII) corresponding to the amino acids referred to as "i" and "i + 4" or "i + 7". Compounds (VI) and (VII) will be those which undergo a subsequent cyclisation step to generate the "L" diradical:

wherein R is₁₉As defined above, Z₃And Z₄Are the same or different and are selected from: halogen-SH, -NHR₂₀、-OH、(C₂-C₁₀) alkyl-SH, (C)₁-C₁₀) alkyl-OH, (C)₁-C₁₀) Alkyl radical-NHR₂₁、C(＝O)OH、(C₁-C₁₀)C(＝O)OH、C(＝O)NHR₂₂、(C₁-C₁₀) Alkyl C (═ O) NHR₂₃、OR₂₄C (═ O) -halogen, C (═ O) -OR₂₅S (═ O) -halogen, S (═ O) -OR₂₆、S(＝O)₂R₂₇Wherein R is₂₀、R₂₁R₂₂、R₂₃、R₂₄、R₂₅R₂₆And R₂₇Is selected from halogen, (C)₁-C₁₀) Alkyl, (C)₂-C₁₀) Alkenyl, and (C)₂-C₁₀) (ii) a single radical of an alkynyl group; known ring systems comprising 3 to 14 carbon atoms, which systems comprise 1 to 3 rings, wherein:

each of the rings is saturated, partially unsaturated, or aromatic;

the rings are separate, partially or fully fused,

each of the members forming the known ring system is selected from: -CH-, -CH₂-, -NH-, -N-, -SH-, -S-, and-O-; and is

The ring system is optionally substituted with one or more groups independently selected from: halogen, -OH, -NH₂-SH, C (═ O) -halogen (C)₁-C₁₀) Haloalkyl, and (C)₁-C₁₀) alkyl-O-; and

(2b) comprising Z₃And Z₄A cyclization step of a coupling reaction between groups; or, alternatively,

(3a) the corresponding amino acids of the peptide are coupled by condensation with a compound of formula (VIII) and a compound of formula (IX), corresponding to the amino acids referred to as "i" and "i + 4" or "i + 7". Compounds (VIII) and (IX) will be compounds that undergo a subsequent cyclisation step to generate the "L" diradical:

wherein R is₁₉As defined above, Z₅And Z₆One of (A) is (C)₂-C₁₀) Alkynyl and the other is (C)₂-C₁₀) Alkyl radical N₃(ii) a And

(3.b) comprises Z₅And Z₆A cyclization step of The condensation of groups by The well-known protocol (e.g., Cu (I) -mediated Huisgen 1, 3-dipolar cycloaddition reaction (also known as "click" reaction)) to generate 1, 4-substituted 1,2, 3-triazole bridges (see Kolb H.C.et. for "The growing impact of click chemistry on discovery", 2003, Drug discovery Today,8(24): 1128-1137).

The method for preparing the peptide according to the second aspect of the present invention comprises coupling the carboxyl group or C-terminus of one amino acid to the amino group or N-terminus of another amino acid by condensation, and repeating the coupling reaction a desired number of times until the desired peptide is obtained.

The compounds of formula (IV), formula (V), formula (VI), formula (VII), formula (VIII) and formula (IX) are commercially available and coupled to already formed parts of the peptide sequence by condensation. These compounds may carry beads for appropriate solid phase synthesis of the peptide, and protecting groups for carboxyl, amino or side chains. Illustrative, non-limiting examples of compounds are: 2- (2 ' -propenyl) alanine, 2- (3 ' -butenyl) glycine, 2- (4 ' -pentenyl) alanine, 2- (6 ' -heptenyl) alanine, 2- (7 ' -octenyl) alanine, and allyl-glycine, 5-azido-norvaline, alpha-propargyl-alanine.

The "coupling" step can be carried out in solid phase according to the scheme "deprotection-washing-coupling-washing", by using the amino acids as defined above and the α - α disubstituted amino acids of formulae (IV) to (IX) in order to condense the carboxyl group of one amino acid with the amino group of another amino acid residue to obtain the desired peptide.

The general principle of solid phase peptide synthesis is to repeat a cycle of deprotection-washing-coupling-washing. The free N-terminal amine of the solid phase linker peptide is coupled to a single N-protected amino acid unit. The unit is then deprotected to expose a new N-terminal amine to which additional amino acids can be attached. Amino acids have reactive moieties at the N-and C-termini, which facilitate amino acid coupling during synthesis. Many amino acids also have reactive side chain functionalities that can interact with the free terminus or other side chain groups during synthesis and peptide extension and negatively impact yield and purity. To facilitate proper amino acid synthesis with minimal side chain reactivity, chemical groups have been developed to bind to specific amino acid functional groups and block or protect the functional groups from non-specific reactions. These protecting groups, although broad in nature, can be divided into three groups: n-terminal protecting groups, C-terminal protecting groups (used primarily for liquid phase synthesis), and side chain protecting groups.

For coupling peptides, the carboxyl group is usually activated. This is important to speed up the reaction. There are two main types of activating groups: carbodiimides and triadimenol (triazolol). However, the use of pentafluorophenyl esters (FDPP, PFPOH) and BOP-Cl is useful for cyclizing the peptide.

Purified individual amino acids are reacted with these protecting groups prior to synthesis and then selectively removed during specific steps of peptide synthesis.

Exemplary resins that may be employed in the present invention include, but are not limited to, (1) alkenyl resins (e.g., REM resins, vinyl sulfone polymer-bound resins, vinyl-polystyrene resins), (2) amine-functionalized resins (e.g., amidine resins, N- (4-benzyloxybenzyl) hydroxylamine polymer-bound, (aminomethyl) polystyrene, (R) - (+) - α -methylbenzylamine polymer-bound, 2-chlorotrityl Knorr resins, 2-N-Fmoc-amino-dibenzosubep-1, 4-diene polymer-bound resins, 4- [4- (1-Fmoc-aminoethyl) -2-methoxy-5-nitrophenoxy-phenoxy resin]Butyrylaminomethyl-polystyrene resin, 4-benzyloxybenzylamine polymer bound, 4-carboxybenzenesulfonamide polymer bound, bis (tert-butoxycarbonyl) isothiourea polymer bound, dimethylaminomethyl-polystyrene, Fmoc-3-amino-3- (2-nitrophenyl) propionic acid polymer bound, N-methylaminomethylated polystyrene, PAL resin, Sieber amide resin, tert-butyl N- (2-mercaptoethyl) carbamate polymer bound, triphenylmethyl chloride-4-carboxamide) polymer bound); (3) IIA Benzylamine (BHA) resin (e.g., 2-chlorobenzhydryl chloride polymer-bound, HMPB-benzhydryl amine polymer-bound, 4-methyldiphenylmethanol polymer-bound, diphenylmethyl chloride polymer-bound, benzhydrylamine polymer-bound); (4) bromine-functionalized resins (e.g., 4- (benzyloxy) benzyl bromide polymer-bound, 4-bromopolystyrene, brominated PPOA resin, brominated Wang resin, bromoacetal polymer-bound, brominated polystyrene, and the like,200Br, polystyrene A-Br for peptide synthesis, selenium bromide polymer conjugated, TentaGel HL-Br, TentaGel MB-Br, TentaGel S-Br); (5) chloromethyl resins (e.g. 5- [4- (chloromethyl) phenyl)]Pentyl radical]Styrene polymer bound, 4- (benzyloxy) benzyl chloride polymer bound, 4-methoxybenzoyl chloride polymer bound); (6) CHO functionalized resins (e.g., (4-formyl-3-methoxyphenoxymethyl) polystyrene, 3-benzyloxybenzaldehyde polymer-bound, 4-benzyloxy-2, 6-dimethoxybenzaldehyde polymer-bound, formyl polystyrene, poly (vinyl chloride-co-vinyl acetate), poly (vinyl acetate-co-vinyl acetate), poly,200CHO, indole resin, polystyrene A-CH (OEt)2, TentaGel HL-CH (OEt) 2); (7) chlorine-functionalized resins (e.g., benzoyl chloride polymer-bound, (chloromethyl) polystyrene, Merrifield resins); n (8) CO2H functionalized resins (e.g., carboxyethyl polystyrene, poly (ethylene-CO-butylene,200COOH, polystyrene AM-COOH, TentaGel HL-COOH, TentaGel MB-COOH, TentaGel S-COOH); (9) Hypo-Gel resin (for example,200FMP、200PHB、200Trt-OH、200 HMB); (10) i-functionalized resins (e.g., 4-iodophenol polymer-bound, iodopolystyrene); Janda-Jels^TM(Amines, JandaJel-NH2, JandaJel-Cl, JandaJel-4-mercaptophenol, JandaJel-OH, JandaJel-1- (3-dimethylaminopropyl) -3-ethylcarbodiimide, JandaJel-1,3,4,6,7, 8-hexahydro-2H-pyrimido- [1,2-a]Pyrimidine, JandaJel-morpholine, JandaJel-polypyridine, JandaJel-triphenylphosphine, JandaJel-Wang); (11) MBHA resin (3[ 4' - (hydroxymethyl) phenoxy)]Propionic acid-4-methylbenzhydrylamine resin, resin with 4- (hydroxymethyl) phenoxyacetic acid polymer bound to MBHA, HMBA-4-methylbenzhydrylamine polymer bound, 4-methylbenzhydrylamine hydrochloride polymer binding capacity (amine)); (12) NH 2-functionalized resin ((aminomethyl) polystyrene, poly (ethylene-co-propylene-co-ethylene),200NH2, polystyrene AM-NH2, 2-aminoethylated polystyrene microspheres, 2-bromoethylated polystyrene microspheres, 2-hydroxyethylated polystyrene microspheres, TentaGel HL-NH2, TentaGel M Br, TentaGel M NH2, TentaGel M OH, TentaGel MB-NH2, TentaGel S-NH2, TentaGel S-NH 2); (13) OH-functionalized resins (e.g., 4-hydroxymethylbenzoic acid polymer-bound, methylol resins, OH-functionalized Wang resins); (14) oxime resins (e.g., 4-chlorobenzophenone oxime polymer-bound, benzophenone oxime polymer-bound, 4-methoxybenzophenone oxime polymer-bound); (15) PEG resins (e.g., ethylene glycol polymer-conjugated); (16) Boc-/Blz peptide synthetic resins (e.g., Boc-Lys (Boc) -Lys [ Boc-Lys (Boc))]-Cys (Acm) -b-Ala-O-PAM resin, Boc-Lys (Fmoc) -Lys [ Boc-Lys (Fmoc)]-b-Ala-O-Pam resin, Boc-Lys (Boc) -Lys [ Boc-Lys (Boc)]-Lys{Boc-Lys(Boc)-Lys[Boc-Lys(Boc)]Resin of } -b-Ala-O-PAM, Boc-Lys(Fmoc)-Lys[Boc-Lys(Fmoc)]-Lys[Boc-Lys(Fmoc)-Lys{Boc-Lys(Fmoc)]Resin of } -b-Ala-O-PAM, Boc-Lys (Boc) -Lys [ Boc-Lys (Boc)]-Lys{Boc-Lys(Boc)-Lys[Boc-Lys(Boc)]-Cys (Acm) -b-Ala-O-PAM resin, pre-filled PAM resin); (17) Fmoc-/t-Bu peptide synthetic resin (e.g., Fmoc-Lys (Fmoc) -Lys [ Fmoc-Lys (Fmoc))]-b-Ala-O-Wang resin, Fmoc-Lys (Fmoc) -Lys [ Fmoc-Lys (Fmoc)]-Lys{Fmoc-Lys(Fmoc)-Lys[Fmoc-Lys(Fmoc)]Resin of } -b-Ala-O-Wang, Pre-filledS trityl resin, prepackageResin, trityl resin preloaded, Wang resin preloaded, trityl resin preloaded with amino alcohol); (19) the thiol-functionalized resin (e.g.,200S-Trt, polystyrene AM-S-trityl, TentaGel HL-S-trityl, TentaGel MB-S-trityl, TentaGel S-S-trityl); and (20) Wang resin (e.g., Fmoc-Ala-Wang resin, Fmoc-Arg (Pbf) -Wang resin, Fmoc-Arg (Pmc) -Wang resin, Fmoc-Asn (Trt) -Wang resin, Fmoc-Asp (OtBu) -Wang resin, Fmoc-Cys (Acm) -Wang resin, Fmoc-Cys (StBu) -Wang resin, Fmoc-Cys (Trt) Wang resin, Fmoc-Gln (Trt) -Wang resin, Fmoc-Glu (OtBu) -Wang resin, Fmoc-Gly-Wang resin, Fmoc-His Trt) -Wang resin, Fmoc-Ile-Wang resin, Fmoc-Leu-Lys resin, Fmoc-Wang resin, (Boc) -Wang resin, Fmoc-Met-D-Wang resin, Fmoc-Phe-Wang resin, Fmoc-Leu-Lys resin, Fmoc-Wang resin, Fmoc-Glu resin, Fmoc-Wang resin, Fmoc resin, F, Fmoc-Pro-Wang resin, Fmoc-Ser (tBu) -Wang resin, Fmoc-Ser (Trt) -Wang resin, Fmoc-Thr (tBu) -Wang resin, Fmoc-Trp (Boc) Wang resin, Fmoc-Trp-Wang resin, Fmoc-Tyr (tBu) -Wang resin, Fmoc-Val-Wang resin.

A "Protecting group" (PG) refers to a group of atoms that, when attached to a reactive group in a molecule, masks, reduces, or prevents that reactivity.

Suitable amino protecting groups include methyl carbamate, ethyl carbamate, 9-fluorenylmethyl carbamate (Fmoc), 9- (2-sulfo) fluorenylmethyl carbamate, 9- (2, 7-dibromo) fluorenylmethyl carbamate, 2, 7-di-tert-butyl- [9- (10, 10-dioxa-10, 10,10, 10-tetrahydrothioxanthyl) ] methyl carbamate (DBD-Tmoc), 4-methoxybenzoylmethyl carbamate (Phenoc), 2,2, 2-trichloroethyl carbamate (Troc), 2-trimethylsilylethyl carbamate (Teoc), 2-phenethyl carbamate (hZ), 1- (1-adamantyl) -1-methylethyl carbamate (Adpoc), 1, 1-dimethyl-2-haloethylcarbamate, 1-dimethyl-2, 2-dibromoethylcarbamate (DB-t-BOC), 1-dimethyl-2, 2, 2-Trichloroethylcarbamate (TCBOC), 1-methyl-1- (4-biphenylyl) ethylcarbamate (Bpoc), 1- (3, 5-di-tert-butylphenyl) -1-methylethylcarbamate (t-Bumeoc), 2- (2 '-and 4' -pyridyl) ethylcarbamate (Pyoc), 2- (N, N-dicyclohexylcarboxamide) ethylcarbamate, tert-butyl carbamate (BOC), 1-adamantylcarbamate (Adoc), Vinyl carbamate (Voc), allyl carbamate (Alloc), 1-isopropyl allyl carbamate (Ipaoc), cinnamyl carbamate (Coc), 4-nitrocinnamyl carbamate (Noc), 8-quinolinyl carbamate, N-hydroxypiperidinyl carbamate, alkyl dithiocarbamate, benzyl carbamate (Cbz), benzyl p-methoxycarbamate (Moz), benzyl p-nitrocarbamate, benzyl p-bromocarbamate, benzyl p-chlorocarbamate, benzyl 2, 4-dichlorocarbamate, benzyl 4-methylsulfinyl carbamate (Msz), 9-anthrylmethyl carbamate, benzhydryl carbamate, 2-methylthioethyl carbamate, 2-methylsulfonyl ethyl carbamate, 2- (p-toluenesulfonyl) ethyl carbamate, [2- (1, 3-dithianyl ] ] carbamic acid methyl ester (Dmoc), 4-methylthiophenyl carbamate (Mtpc), 2, 4-dimethylthiophenyl carbamate (Bmpc), 2-phosphoniuylethyl carbamate (Peoc), 2-triphenylphosphonylisopropyl carbamate (Ppoc), 1-dimethyl-2-cyanoethyl carbamate, m-chloro-p-acyloxycarbamic acid benzyl ester, p- (dihydroxyboryl) carbamic acid benzyl ester, 5-benzoxazolyl methyl carbamate, 2- (trifluoromethyl) -6-chromonylmethylcarbamate (Tcroc), m-nitrophenyl carbamate, 3, 5-dimethoxycarbamic acid benzyl ester, o-nitrocarbamic acid benzyl ester, 3, 4-dimethoxy-6-nitrocarbamic acid benzyl ester, Phenyl (o-nitrophenyl) methylcarbamate, phenothiazinyl- (10) -carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl derivative, N' -phenylaminothiocarbonyl derivative, tert-amyl carbamate, S-benzylthiocarbamate, p-cyanocarbamate, cyclobutyl carbamate, cyclohexyl carbamate, cyclopentyl carbamate, cyclopropylmethylcarbamate, benzyl p-decyloxycarbamate, 2-dimethoxycarbonylvinylcarbamate, benzyl o- (N, N-dimethylformylamino) carbamate, 1-dimethyl-3- (N, N-dimethylformylamino) propylcarbamate, 1-dimethylpropynylcarbamate, bis (2-pyridyl) methylcarbamate, phenothiazinyl- (10) -carbonyl derivative, N '-p-toluenesulfonylaminocarbonyl derivative, N' -phenylaminothiocarbonyl derivative, tert-amyl carbamate, S-benzylthiocarbamate, p-cyanocarbamate, cyclobutylcarbamate, cyclohexylcarbamate, cyclopentylcarbamate, 2-furyl methylcarbamate, 2-iodoethylcarbamate, isobornyl carbamate, isobutyl carbamate, isonicotinamidoformate, benzyl p- (p-methoxyphenylazo) carbamate, 1-methylcyclobutyl carbamate, 1-methylcyclohexyl carbamate, 1-methyl-1-cyclopropylmethyl carbamate, 1-methyl-1- (3, 5-dimethoxyphenyl) ethyl carbamate, 1-methyl-1- (p-phenylazophenyl) ethyl carbamate, 1-methyl-1-phenylethyl carbamate, 1-methyl-1- (4-pyridyl) ethyl carbamate, phenyl carbamate, benzyl p- (phenylazo) carbamate, methyl-1- (4-pyridyl) ethyl carbamate, methyl-1- (3-dimethoxyphenyl) carbamate, methyl-1- (p-phenylazo) carbamate, methyl-1- (4-pyridyl) ethyl carbamate, methyl-2-methyl-carbamate, methyl-2-iodoethyl carbamate, isob, 2,4, 6-tri-tert-butylphenylcarbamate, benzyl 4- (trimethylammonium) carbamate, benzyl 2,4, 6-trimethylcarbamate, formamide, acetamide, chloroacetamide, trichloroacetamide, trifluoroacetamide, phenylacetamide, 3-phenylacrylamide, picolinamide, 3-pyridinecarboxamide, N-benzoylphenylalanyl derivative, benzamide, p-phenylbenzamide, o-nitroacetoamide, o-nitrophenoxyacetamide, acetoacetamide, (N' -dithiobenzyloxycarbonylamino) acetamide, 3- (p-hydroxyphenyl) propionamide, 3- (o-nitrophenyl) propionamide, 2-methyl-2- (o-nitrophenoxy) propionamide, 2-methyl-2- (o-phenylazophenoxy) propionamide, and mixtures thereof, 4-chlorobutanamide, 3-methyl-3-nitrobutanamide, o-nitrocinnamamide, N-acetylmethionine derivatives, o-nitrobenzamide, o- (benzoyloxymethyl) benzamide, 4, 5-diphenyl-3-oxazolin-2-one, N-phthalimide, N-dithiosuccinimide (Dts), N-2, 3-diphenylmaleimide, N-2, 5-dimethylpyrrole, N-1,1,4, 4-tetramethyldisilylazacyclopentane adduct (STABASE), 5-substituted 1, 3-dimethyl-1, 3, 5-triazacyclohexan-2-one, 5-substituted 1, 3-dibenzyl-1, 3, 5-triazacyclohex-2-one, 1-substituted 3, 5-dinitro-4-pyridone, N-methylamine, N-allylamine, N- [ 2-trimethylsilyl) ethoxy ] methylamine (SEM), N-3-acetoxypropylamine, N- (1-isopropyl-4-nitro-2-oxo-3-pyrrolin-3-yl) amine, quaternary ammonium salts, N-benzylamine, N-bis (4-methoxyphenyl) methylamine, N-5-dibenzocycloheptylamine, N-triphenylmethylamine (Tr), N- [ ((4-methoxyphenyl) benzhydryl ] amine (MMTr), N-9-phenylfluoroamine (PhF), N-2, 7-dichloro-9-fluoromethylene amine, N-ferrocenylmethylamino (Fcm), N-2-picolylamino N '-oxide, N-1, 1-dimethylthiomethyleneamine, N-benzylidene amine, N-p-methoxybenzylideneamine, N-diphenylmethyleneamine, N- [ ((2-pyridyl) trimethylphenyl ] methyleneamine, N- (N', N '-dimethylaminomethylene) amine, N' -isopropylidenediamine, N-p-nitrobenzylideneamine, N-salicylidene amine, N-5-chlorosalicylideneamine, N- (5-chloro-2-hydroxyphenyl) phenylmethylamine, N-cyclohexylimine, N- (5, 5-dimethyl-3-oxo-1-cyclohexenyl) amine, N-borane derivatives, N-diphenylboronic acid derivatives, N- [ phenyl (chromium or tungsten pentacarbonyl) carbonyl ] amines, N-copper chelates, N-zinc chelates, N-nitramines, N-nitrosamines, amine N-oxides, diphenylphosphinamides (Dpp), dimethylthiophosphonamides (Mpt), diphenylphosphinamides (Ppt), dialkylphosphoramides, dibenzylphosphoramidates, diphenylphosphoramidates, benzenesulfenamides, o-nitrobenzsulfenamides (Nps), 2, 4-dinitrobenzenesulfenamides, pentachlorobenzenesulfinamides, 2-nitro-4-methoxybenzenesulfinamides, triphenylmethylsulfinamides, 3-nitropyridine sulfenamides (Npys), p-toluenesulfonamides (Ts), benzenesulfonamides, 2,3, 6-trimethyl-4-methoxybenzenesulfonamides (Mtr), 2,4, 6-trimethoxybenzenesulfonamide (Mtb), 2, 6-dimethyl-4-methoxybenzenesulfonamide (Pme), 2,3, 5, 6-tetramethyl-4-methoxybenzenesulfonamide (Mte), 4-methoxybenzenesulfonamide (Mbs), 2,4, 6-trimethylbenzenesulfonamide (Mts), 2, 6-dimethoxy-4-methylbenzenesulfonamide (iMds), 2,5, 7, 8-pentamethylbenzodihydropyran-6-sulfonamide (Pmc), methanesulfonamide (Ms), β -trimethylsilylethanesulfonamide (SES), 9-anthracenesulfonamide, 4- (4 ', 8' -dimethoxynaphthylmethyl) benzenesulfonamide (DNMBS), benzylsulfonamide, trifluoromethylsulfonamide, and benzoylmethanesulfonamide.

Examples of suitably protected carboxylic acids further include, but are not limited to, silyl, alkyl, alkenyl, aryl, and arylalkyl protected carboxylic acids. Examples of suitable silyl groups include trimethylsilyl, triethylsilyl, t-butyldimethylsilyl, t-butyldiphenylsilyl, triisopropylsilyl, and the like. Examples of suitable alkyl groups include methyl, benzyl, p-methoxybenzyl, 3, 4-dimethoxybenzyl, trityl, tert-butyl, tetrahydropyran-2-yl. Examples of suitable alkenyl groups include allyl. Examples of suitable aryl groups include optionally substituted phenyl, biphenyl or naphthyl. Examples of suitable arylalkyl groups include optionally substituted benzyl (e.g., p-methoxybenzyl (MPM), 3, 4-dimethoxybenzyl, o-nitrobenzyl, p-halobenzyl, 2, 6-dichlorobenzyl, p-cyanobenzyl), and 2-and 4-methylpyridine.

In a third aspect, the present invention provides a fusion peptide comprising a peptide as defined in the first or second aspect of the invention, or in any embodiment of the first or second aspect of the invention, and a cell penetrating peptide.

In the present invention, the term "Cell penetrating peptide" (CPP) refers to a short peptide that promotes cellular uptake of various molecular cargo (from nano-sized particles to large fragments of small chemical molecules and DNA). The "cargo" is associated with the peptide via the C-terminus or N-terminus, or by chemical linkage via a covalent bond, or by non-covalent interactions. The function of a CPP is to deliver cargo into cells, a process that typically occurs through endocytosis of the cargo into delivery vehicles for research and medicine. Current use is limited by the lack of cell specificity in CPP-mediated cargo delivery and the inadequate understanding of its uptake pattern. CPPs generally have an amino acid composition of: the amino acid composition comprises a high relative abundance of positively charged amino acids, such as lysine or arginine, or a sequence having an alternating pattern comprising polar/charged amino acids and non-polar hydrophobic amino acids. These two types of structures are referred to as polycationic or amphiphilic, respectively. The third class of CPPs are hydrophobic peptides that contain only non-polar residues, have a low net charge or have hydrophobic amino acid groups that are critical for cellular uptake. Conjugation of CPPs to the Peptides provided by the present invention can be carried out according to well-known conventional protocols (e.g., solid phase Synthesis or solution selective capping) (see Copolovici D.M.et. al., "Cell-peptide Peptides: Design, Synthesis, and Applications", 2014, ACS Nano, 2014, 8(3), pp 1972-.

In another embodiment of the third aspect of the present invention provided above or below, the cell penetrating peptide is a polycationic CPP. In another embodiment of the third aspect of the invention, optionally in combination with any of the embodiments provided above or below, the cell penetrating peptide is poly arg (polyarg) or, alternatively, is penetrating.

In one embodiment of the third aspect of the invention, the fusion peptide is as set forth in SEQ ID NO: 8. 9 or 29:

SEQ ID NO: 8 (hereinafter also referred to as "LLCb 01")

Arg-Arg-Arg-Arg-Arg-Arg-Arg-Ser-Lys-Ala-Pro-Lys-Val-Val-Ile-Leu-Ser-Lys-Ala-Leu-Glu-Tyr-Leu-Gln-Ala

SEQ ID NO: 9 (hereinafter also referred to as "LLCb 02")

Arg Gln Ile Lys Trp Phe Gln Asn Arg Arg Met Lys Trp Lys Lys Ser LysAla Pro Lys Val Val Ile Leu Ser Lys Ala Leu Glu Tyr Leu Gln Ala

SEQ ID NO: 29 (hereinafter also referred to as "intwtL 05"):

Arg Arg Arg Arg Arg Arg Arg Arg Lys Arg Arg Asn Asp Leu Arg Ser ArgPhe Leu Ala Leu Arg Asp Gln

in a fourth aspect, the present invention provides a pharmaceutical composition.

The expression "therapeutically effective amount" as used herein refers to an amount of a compound which, when administered, is sufficient to prevent the development of, or alleviate to some extent, one or more symptoms of the disease to be addressed. Of course, the specific dose of peptide administered in accordance with the present invention will depend on the particular circumstances surrounding the case, including the compound administered, the route of administration, the particular condition being treated, and similar considerations.

The expression "pharmaceutically acceptable excipient or carrier" refers to a pharmaceutically acceptable material, composition or vehicle. Each component must be pharmaceutically acceptable in the sense of being compatible with the other ingredients of the pharmaceutical composition. It must also be suitable for use in contact with the tissues or organs of human and non-human animals without excessive toxicity, irritation, allergic response, immunogenicity, or other problems or complications commensurate with a reasonable benefit/risk ratio. Examples of suitable pharmaceutically acceptable excipients are solvents, dispersion media, diluents or other liquid vehicles, dispersion or suspension aids, surfactants, isotonicity agents, thickening or emulsifying agents, preservatives, solid binders, lubricants and the like. Unless any conventional excipient medium is incompatible with a substance or derivative thereof, e.g., by producing any undesirable biological effect or interacting in a deleterious manner with any other component of a pharmaceutical composition, its use is considered to be within the scope of the present invention.

The formulations of the pharmaceutical compositions described herein may be prepared by any method known or later developed in the pharmacological arts. Generally, such a preparation method comprises the steps of: the active ingredient (the peptide) is associated with excipients and/or one or more other auxiliary ingredients, and then, if necessary and/or desired, the product is shaped and/or packaged into the desired single-or multi-dose units.

The pharmaceutical compositions of the present invention may be manufactured, packaged and/or sold in bulk as a single unit dose, and/or as multiple single unit doses. As used herein, a "unit dose" is a discrete amount of a pharmaceutical composition that contains a predetermined amount of active ingredient. The amount of active ingredient is generally equal to the dose of active ingredient to be administered to the subject and/or an appropriate fraction of such dose, e.g., half or one third of such dose.

The relative amounts of the active ingredient (i.e., the peptide as defined in any of the foregoing aspects and embodiments), pharmaceutically acceptable excipient, and/or any other ingredient in the pharmaceutical composition of the invention will vary depending on the identity, size and/or condition of the subject being treated, and also depending on the route of administration of the composition.

Pharmaceutically acceptable excipients used in the manufacture of pharmaceutical compositions include, but are not limited to, inert diluents, dispersing and/or granulating agents, surfactants and/or emulsifiers, disintegrating agents, binders, preservatives, buffers, lubricants, and/or oils. Such excipients may optionally be included in the formulations of the present invention. Excipients such as cocoa butter and suppository waxes, coloring, coating, sweetening, flavoring and perfuming agents may be present in the composition according to the judgment of the formulator.

Exemplary diluents include, but are not limited to, calcium carbonate, sodium carbonate, calcium phosphate, dicalcium phosphate, calcium sulfate, dicalcium phosphate, sodium phosphate lactose, sucrose, cellulose, microcrystalline cellulose, kaolin, mannitol, sorbitol, inositol, sodium chloride, dry starch, corn starch, powdered sugar, and combinations thereof.

Exemplary granulating and/or dispersing agents include, but are not limited to, potato starch, corn starch, tapioca starch, sodium starch glycolate, clays, alginic acid, guar gum, citrus pulp, agar, bentonite, cellulose and wood products, natural sponges, cation exchange resins, calcium carbonate, silicates, sodium carbonate, cross-linked polyvinylpyrrolidone (crospovidone), sodium carboxymethyl starch (sodium starch glycolate), carboxymethyl cellulose, cross-linked sodium carboxymethyl cellulose (cross-linked carboxymethyl cellulose), methyl cellulose, pregelatinized starch (starch 1500), microcrystalline starch, water insoluble starch, calcium carboxymethyl cellulose, magnesium aluminum silicate (Veegum)), sodium lauryl sulfate, quaternary ammonium compounds, and combinations thereof.

Exemplary surfactants and/or emulsifiers include, but are not limited to, natural emulsifiers (e.g., gum arabic, agar, alginic acid, sodium alginate, tragacanth, carrageenan (chondrux), cholesterol, xanthan gum, pectin, gelatin, egg yolk, casein, lanolin, cholesterol, waxes, and lecithin), colloidal clays (e.g., bentonite [ aluminum silicate ] and magnesium aluminosilicate [ magnesium aluminum silicate ]), long chain amino acid derivatives, high molecular weight alcohols (e.g., stearyl alcohol, cetyl alcohol, oleyl alcohol, glyceryl triacetate monostearate, ethylene glycol distearate, glyceryl monostearate and propylene glycol monostearate, polyvinyl alcohol), carbomers (e.g., carboxypolymethylene, polyacrylic acid, acrylic polymers, and carboxyvinyl polymers), carrageenan, cellulose derivatives (e.g., sodium carboxymethylcellulose, sodium cellulose, sodium carboxymethylcellulose, sodium alginate, and mixtures thereof, Powdered cellulose, hydroxymethylcellulose, hydroxypropylcellulose, hydroxypropylmethylcellulose, methylcellulose), sorbitan fatty acid esters (e.g., polyoxyethylene sorbitan monolaurate [ tween 20], polyoxyethylene sorbitan [ tween 60], polyoxyethylene sorbitan monooleate [ tween 80], sorbitan monopalmitate [ span 40], sorbitan monostearate [ span 60], sorbitan tristearate [ span 65], glycerol monooleate, sorbitan monooleate [ span 80]), polyoxyethylene esters (e.g., polyoxyethylene monostearate [ Myrj 45], polyoxyethylene hydrogenated castor oil, polyethoxylated castor oil, polyoxyl stearate, and Solutol), sucrose fatty acid esters, polyethylene glycol fatty acid esters (e.g., Cremophor), polyoxyethylene ethers (e.g., polyoxyethylene lauryl ether [ Brij 30]), poly (vinyl pyrrolidone), diethylene glycol monolaurate, triethanolamine oleate, sodium oleate, potassium oleate, ethyl oleate, oleic acid, ethyl laurate, sodium lauryl sulfate, Pluronic F68 (Pluronic F68), Poloxamer 188(Poloxamer 188), cetrimide, cetylpyridinium chloride, benzalkonium chloride, docusate sodium, and the like, and/or combinations thereof.

Exemplary binders include, but are not limited to, starch (e.g., corn starch and starch paste); gelatin; sugars (e.g., sucrose, glucose, dextrose, dextrin, molasses, lactose, lactitol, mannitol); natural and synthetic gums (e.g., gum arabic, sodium alginate, irish moss extract, panval gum (panwar gum), ghatti gum (ghatti gum), mucilage of ixalpel shells (mucous of isapol husks), carboxymethyl cellulose, methyl cellulose, ethyl cellulose, hydroxyethyl cellulose, hydroxypropyl methyl cellulose, microcrystalline cellulose, cellulose acetate, polyvinyl pyrrolidone), magnesium aluminum silicate (magnesium aluminum silicate), and larch arabinogalactan); an alginate; polyethylene oxide; polyethylene glycol; inorganic calcium salts; silicic acid; polymethacrylates; a wax; water; an alcohol; and combinations thereof.

Exemplary preservatives can include antioxidants, chelating agents, antimicrobial preservatives, antifungal preservatives, alcoholic preservatives, acidic preservatives, and other preservatives. Exemplary antioxidants include, but are not limited to, alpha-tocopherol, ascorbic acid, ascorbyl palmitate, butylated hydroxyanisole, butylated hydroxytoluene, monothioglycerol, potassium metabisulfite, propionic acid, propyl gallate, sodium ascorbate, sodium bisulfite, sodium metabisulfite, and sodium sulfite. Exemplary chelating agents include ethylenediaminetetraacetic acid (EDTA), citric acid monohydrate, edetate disodium, edetate dipotassium, edetic acid, fumaric acid, malic acid, phosphoric acid, edetate sodium, tartaric acid, and edetate trisodium. Exemplary antimicrobial preservatives include, but are not limited to, benzalkonium chloride, benzethonium chloride, benzyl alcohol, bronopol, cetrimide, cetylpyridinium chloride, chlorhexidine, chlorobutanol, chlorocresol, chloroxylenol, cresol, ethanol, glycerin, hexabutyldine, imidurea, phenol, phenoxyethanol, phenylethyl alcohol, phenylmercuric nitrate, propylene glycol, and thimerosal. Exemplary antifungal preservatives include, but are not limited to, butyl paraben, methyl paraben, ethyl paraben, propyl paraben, benzoic acid, hydroxybenzoic acid, potassium benzoate, potassium sorbate, sodium benzoate, sodium propionate, and sorbic acid. Exemplary alcohol preservatives include, but are not limited to, ethanol, polyethylene glycol, phenol, phenolic compounds, bisphenol, chlorobutanol, hydroxybenzoate, and phenylethyl alcohol. Exemplary acidic preservatives include, but are not limited to, vitamin a, vitamin C, vitamin E, beta-carotene, citric acid, acetic acid, dehydroacetic acid, ascorbic acid, sorbic acid, and phytic acid. Other preservatives include, but are not limited to, tocopherol acetate, deferoxamine mesylate, cetrimide, Butylated Hydroxyanisole (BHA), Butylated Hydroxytoluene (BHT), ethylenediamine, Sodium Lauryl Sulfate (SLS), Sodium Lauryl Ether Sulfate (SLES), sodium bisulfite, sodium metabisulfite, potassium sulfite, potassium metabisulfite, galanthamine complex (Glydant Plus), fenoxanil (Phenonip), methyl paraben, gmole 115 (germanl 115), tremella ii (germben ii), nylon (Neolone), carbazone (Kathon), and isol (Euxyl). In certain embodiments, the preservative is an antioxidant. In other embodiments, the preservative is a chelating agent.

Exemplary buffering agents include, but are not limited to, citrate buffer solutions, acetate buffer solutions, phosphate buffer solutions, ammonium chloride, calcium carbonate, calcium chloride, calcium citrate, calcium glubionate, calcium glucoheptonate, calcium gluconate, D-gluconic acid, calcium glycerophosphate, calcium lactate, propionic acid, calcium levulinate, valeric acid, dibasic calcium phosphate, phosphoric acid, tribasic calcium phosphate, basic calcium phosphate, potassium acetate, potassium chloride, potassium gluconate, potassium mixtures, dipotassium hydrogen phosphate, potassium dihydrogen phosphate, potassium phosphate mixtures, sodium acetate, sodium bicarbonate, sodium chloride, sodium citrate, sodium lactate, disodium hydrogen phosphate, sodium dihydrogen phosphate, sodium phosphate mixtures, tromethamine, magnesium hydroxide, aluminum hydroxide, alginic acid, pyrogen-free water, isotonic saline, ringer's solution, ethanol, and combinations thereof.

Exemplary lubricants include, but are not limited to, magnesium stearate, calcium stearate, stearic acid, silicon dioxide, talc, malt, glyceryl behenate, hydrogenated vegetable oil, polyethylene glycol, sodium benzoate, sodium acetate, sodium chloride, leucine, magnesium lauryl sulfate, sodium lauryl sulfate, and combinations thereof.

Exemplary oils include, but are not limited to, almond oil, apricot kernel oil, avocado oil, babassu kernel oil, bergamot oil, black currant seed oil, borage oil, juniper oil, chamomile oil, canola oil, caraway oil, babassu oil, castor oil, cinnamon oil, cocoa butter, coconut oil, cod liver oil, coffee oil, corn oil, cottonseed oil, emu oil, eucalyptus oil, evening primrose oil, fish oil, linseed oil, geraniol oil, gourd oil, grapeseed oil, hazelnut oil, hyssop oil, isopropyl myristate oil, jojoba oil, macadamia nut oil, lavandin oil, lavender oil, lemon oil, mountain nut oil, waiian oil, macadamia nut oil, mallow, mango seed oil, meadowfoam seed oil, mink oil, nutmeg oil, olive oil, orange oil, fish oil, palm kernel oil, peanut oil, poppy seed oil, peanut oil, olive oil, orange oil, fish oil, palm kernel oil, poppy seed oil, peanut oil, pumpkin seed oil, rapeseed oil, rice bran oil, rosemary oil, safflower oil, sandalwood oil, camellia oil, savory oil, sea buckthorn oil, sesame oil, shea butter, silicone oil, soybean oil, sunflower oil, tea tree oil, thistle oil, toon oil, vetiver oil, walnut oil, and wheat germ oil. Exemplary oils include, but are not limited to, butyl stearate, caprylic triglyceride, capric triglyceride, cyclomethicone, diethyl sebacate, dimethicone 360, isopropyl myristate, mineral oil, octyldodecanol, oleyl alcohol, silicone oil, and combinations thereof.

Liquid dosage forms for oral and parenteral administration include, but are not limited to, pharmaceutically acceptable liposomal emulsions, microemulsions, solutions, suspensions, syrups, and elixirs. In addition to the active ingredient, the liquid dosage forms may contain inert diluents commonly used in the art such as, for example, water or other solvents, solubilizing agents and emulsifiers such as ethyl alcohol, isopropyl alcohol, ethyl carbonate, ethyl acetate, benzyl alcohol, benzyl benzoate, propylene glycol, 1, 3-butylene glycol, dimethylformamide, oils (in particular, cottonseed, groundnut, corn, germ, olive, castor, and sesame oils), glycerol, tetrahydrofuryl alcohol, polyethylene glycols and fatty acid esters of sorbitan, and mixtures thereof. In addition to inert diluents, oral compositions can also contain adjuvants such as wetting agents, emulsifying and suspending agents, sweetening, flavoring, and perfuming agents. In certain embodiments for parenteral administration, the inventionConjugates with solubilizing agents (e.g., polyethoxylated castor oil (e.g., CREMOPHOR)^TM) Alcohols, oils, modified oils, glycols, polysorbates, cyclodextrins, polymers, and combinations thereof).

Injectable preparations, for example sterile injectable aqueous or oleaginous suspensions, may be formulated according to the known art using suitable dispersing or wetting agents and suspending agents. The sterile injectable preparation may be a sterile injectable solution, suspension or emulsion in a non-toxic parenterally-acceptable diluent or solvent, for example, as a solution in 1, 3-butanediol. Among the acceptable vehicles and solvents that may be used are water, ringer's solution (u.s.p.), and isotonic sodium chloride solution. In addition, sterile, fixed oils are conventionally employed as a solvent or suspending medium. For this purpose, any bland fixed oil may be employed including synthetic mono-or diglycerides. In addition, fatty acids such as oleic acid find use in the preparation of injectables. Alternatively, the formulation may be in the form of liposomes.

The injectable formulations can be sterilized, for example, by filtration through a bacterial-retaining filter, or by the addition of sterilizing agents in the form of sterile solid compositions which can be dissolved or dispersed in sterile water or other sterile injectable medium prior to use.

In order to prolong the effect of a drug, it is often desirable to slow the absorption of the drug from subcutaneous or intramuscular injection. This can be achieved by using a liquid suspension of crystalline or amorphous material which is poorly water soluble. The rate of absorption of the drug then depends on its rate of dissolution, which in turn may depend on crystal size and crystalline form. Alternatively, delayed absorption of a parenterally administered drug form is achieved by dissolving or suspending the drug in an oil vehicle.

Oral solid dosage forms include capsules, tablets, pills, powders and granules. In such solid dosage forms, the active ingredient is admixed with at least one inert pharmaceutically acceptable excipient, such as sodium citrate or calcium hydrogen phosphate and/or a) fillers or extenders, such as starches, lactose, sucrose, glucose, mannitol and silicic acid; b) binders such as carboxymethylcellulose, alginates, gelatin, polyvinylpyrrolidone, sucrose and gum arabic; c) humectants, such as glycerol; d) disintegrating agents, such as agar-agar, calcium carbonate, potato or tapioca starch, alginic acid, certain silicates, and sodium carbonate; e) solution retarders, such as paraffin; f) absorption accelerators, such as quaternary ammonium compounds; g) wetting agents, such as cetyl alcohol and glyceryl monostearate; h) absorbents such as kaolin and bentonite clay; and i) lubricants, such as talc, calcium stearate, magnesium stearate, solid polyethylene glycols, sodium lauryl sulfate and mixtures thereof. In the case of capsules, tablets and pills, the dosage forms may contain buffering agents.

Solid compositions of a similar type may be employed as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or 1, 4-galactosylglucose (mil sugar) and high molecular weight polyethylene glycols. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings and other coatings well known in the pharmaceutical formulating art. They may optionally contain opacifying agents and may have compositions that release the active ingredient only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes. Solid compositions of a similar type may be employed as fillers in soft-filled and hard-filled gelatin capsules using excipients such as lactose or 1, 4-galactosylglucose and high molecular weight polyethylene glycols.

The peptides of the invention may be in the form of microcapsules with one or more excipients as described above. In one embodiment, the peptides of the invention are formulated in liposomes. Solid dosage forms of tablets, dragees, capsules, pills, and granules can be prepared with coatings and shells such as enteric coatings, release-controlling coatings, and other coatings well known in the pharmaceutical formulating art. In such solid dosage forms, the active ingredient may be mixed with at least one inert diluent, for example sucrose, lactose or starch. Such dosage forms may conventionally contain, in addition to the inert diluent, other substances such as tableting lubricants and other tableting aids, for example magnesium stearate and microcrystalline cellulose. In the case of capsules, tablets and pills, the dosage forms may contain buffering agents. They may optionally contain opacifying agents and may have compositions that release the active ingredient only, or preferably, in a certain part of the intestinal tract, optionally in a delayed manner. Examples of embedding compositions that may be used include polymeric substances and waxes.

It is to be understood that the peptides and pharmaceutical compositions of the invention may be used in combination therapy. The particular combination of therapies (treatments or procedures) employed in the combination regimen will take into account the compatibility of the treatments and/or procedures required and the desired therapeutic effect to be achieved. It will be appreciated that the therapies employed may achieve the desired effect for the same purpose (e.g., the conjugate of the invention for detecting a tumor may be administered simultaneously with another agent for detecting a tumor), or they may achieve different effects (e.g., control of any side effects).

The pharmaceutical compositions of the present invention may be administered alone or in combination with one or more other therapeutic agents. "in combination with … …" does not mean that the agents must be administered and/or formulated simultaneously for delivery together, although such delivery methods are within the scope of the present invention. The composition may be administered simultaneously with, prior to, or subsequent to one or more other desired therapeutic or medical procedures. Typically, each agent will be administered in a dose and/or schedule determined for that agent. In addition, the present invention encompasses the delivery of a peptide or pharmaceutical composition in combination with an agent that can improve its bioavailability, reduce and/or alter its metabolism, inhibit its excretion, and/or alter its distribution in the body.

The particular combination of therapies employed in the combination regimen will take into account the desired treatment and/or compatibility of the procedure and/or the desired therapeutic effect to be achieved. It will be appreciated that the therapies employed may achieve the desired effect on the same condition (e.g., the polypeptides of the invention may be administered simultaneously with another bioactive agent used to treat the same condition), and/or they may achieve different effects (e.g., control of any side effects). It is also understood that the bioactive agents used in the combination can be administered together in a single composition or separately in different compositions.

Therein, the expression "in combination with … …" also covers the possibility of conjugating (by chemical-physical interaction) the peptide of the invention with any other agent mentioned above and below which may be a therapeutic agent or an agent for improving the characteristics (e.g. bioavailability) of the peptide.

In one embodiment, the peptides of the invention are administered in combination with one or more anti-cancer agents. The anticancer agent may be, for example, methotrexate (methotrexate), vincristine (vincristine), doxorubicin (adriamycin), cisplatin (cissplatin), sugar-free chloroethylnitrosurea, 5-fluorouracil, mitomycin C (mitomycin C), bleomycin (bleomycin), doxorubicin (doxorubicin), dacarbazine (dacarbazine), taxol (taxol), fragiline (fragylamine), meglumine (meglumine GLA), valrubicin, carmustine (carmustine) and polifeprosan (polifeprosan), MMI270, BAY 12-9566, RAS farnesyltransferase inhibitor (RAS farnesyltransferase inhibitor), farnesyltransferase inhibitor, MMP, MTA/LY231514, MTA 4618/lomethaxol, Lorentiprone (Lorentiprone), vincristine (vinristine), gentamycin C (mitomycin C), mitomycin C (mitomycin C), bleomycin (PKC), PKC (mitomycin C), PKC (doxoramin) and Toxolone (TM) (thiogalactor) 3/TME) and (TM) (Glycerin) and valtrexate), wherein the anticancer agent may be selected from the group consisting of methotrexate (loxacin, wherein the group of the group I, wherein the group of the group I, the group of the group is selected from the group, Suramin hexasodium salt (Metaret)/Suramin (Suramin), Batimastat (Batimastat), E7070, BCH-4556, CS-682, 9-AC, AG3340, AG3433, Incel/VX-710, VX-853, ZD0101, ISI641, ODN 698, TA 2516/mamiostat (Marmistat), BB 2516/mamiostat, CDP 845, D2163, PD 805, DX895 if, Lactobacillus preparation 2202 DP (Lemonal DP 2202), FK 317, Bisibanil/OK-432, AD 32/Valrubicin (Valrubicin), Metastron/strontium derivative (strontiderivative), Temodal/Temozolomide (Temod)/Temozolomide (Temolozolomide), doxorubicin (Evoacaracil)/doxoramide (Paclitaxel), Paclitaxel (Taxillol (Taxotex), Paclitaxel (Taxillol)/Paclitaxel (Taxillol), Paclitaxel (Taxillol)/Paclitaxel (Taxol), Paclitaxel (Taxol (Taxillol)/Paclitaxel (Taxol) liposome (Taxol), Paclitaxel (Taxillol)/Paclitaxel), Paclitaxel (Taxol) and Taxillol (Taxillol) liposome), Fluorofenolone (Furtulon)/deoxyfluorouridine (Doxifluridine), Clerodendron (Cyclopax)/oral paclitaxel, oral taxane (Taxoid), SPU-077/cisplatin, HMR 1275/fusidic (Flavopiridol), CP-358(774)/EGFR, CP-609(754)/RAS oncogene inhibitor, BMS-182751/oral platinum, UFT (Tegafur)/uracil), Ergamisol/Levamisole (Levamisole), Eniluracil (Eniluracil)/C85/5 FU enhancer, Kempto (Camptoto)/Levamisole, Camptosar/Irinotecan (Irinotan), Dosimodex (Tuxiex)/Ralittrexed (Ralittrexed), Leustin/Clartibine (Clentidine), Paxex/paclitaxel, doxin/doxorubine (Doxix), Doxiflurididine (doxorubicin)/doxorubicin (Cayleridol)/oral paclitaxel), Lipolax (Cayle (Caxix)/Raylexlrubicin), Lipocaline (Lipocalin)/Ralitmustine), Lipocalin (Taxix) and/Lipocalin, Fudahua (Fludara)/Fludarabine (Fludarabine), epirubicin (Pharmarubicin)/epirubicin, cytarabine (Depocyt), ZD1839, LU 79553/bisnaphthoylimide (Bis-Naphtalimide), LU 103793/dolastatin (Dolastain), regular script (Caetyx)/liposomal doxorubicin, Gemzar (Gemczar)/Gemcitabine (Gemcitabine), ZD 0473/Anormed, YM 116, iodine particles, CDK4 and CDK2 inhibitors, PARP inhibitors, D4809/D-noramide (Dexisnex), Ifes/mesna (Mesnex)/ifosfamide (Ifosampamide), Wilminum (Vumon)/Teniposide (Teniposide), Burdin (Paraclin)/Carboplatin (Carboplatin), ventalin/E, Ventripin/Ethicin, Ethicin (Virgaline), Docetaxel (Taxorubine, D933 1), Docetaxel (D-D), Docetaxel (D), D-D, D-D, D-D, D-D, Taxane analogs, nitrosoureas, alkylating agents such as melphalan (melphelan) and cyclophosphamide, Aminoglutethimide (aminooglutenimide), asparaginase, busulfan, carboplatin, chlorambucil, cytarabine hydrochloride, actinomycin D, daunorubicin hydrochloride, Estramustine sodium phosphate (Estramustine phosphate sodium), etoposide (VP16-213), floxuridine, fluorouracil (5-FU), flutamide, hydroxyurea (hydroxyurea), ifosfamide, interferon alpha-2 a, interferon alpha-2 b, leuprolide acetate (LHRH-releasing factor analog), Lomustine (Lomustine) (NUCCC), mechlorethamine hydrochloride (nitrogen mustard), mercaptopurine, Mesna (Mesna), Mitotane (Mitotane) (o.p-DDD), mitoxantrone hydrochloride, Octreotide (Octretide), Plicamycin (Procarbazine), Procarbazine hydrochloride (Procarbazine), streptozocin (Progestrin hydrochloride), streptozocin (HCL), and other compounds, Tamoxifen citrate (Tamoxifen citrate), thioguanine, Thiotepa (Thiotepa), vinblastine sulfate, Amsacrine (Amsacrine; m-AMSA), Azacitidine (Azacitidine), erythropoietin (ertropoietin), Hexamethylmelamine (HMM), interleukin 2, Mitoguazone (Mitoguazone) (methyl GAG; methylglyoxal dipropionazone; MGBG), Pentostatin (pentastatin) (2 '-desoxysyndiomycin, 2' -deoxynofuromycin), Semustine (Semustine) (methyl CCNU), Teniposide (Teniposide; VM-26) or vindesine sulfate, signal transduction inhibitors (e.g., MEK, BRAF, AKT, her2, mTOR, and PI3K inhibitors), but are not limited thereto.

As shown below, the peptides of the first aspect of the invention are useful in the treatment of a cancer selected from: leukemia, myeloma, breast cancer, and lung cancer, such as small cell lung cancer. In another embodiment, the peptide of the second aspect of the invention is useful in the treatment of myeloma and lung cancer, for example small cell lung cancer.

Throughout the description and claims the word "comprise" and variations of the word are not intended to exclude other technical features, additives, components or steps. Further, the word "comprising" covers the case of "consisting of … …". Additional objects, advantages and features of the invention will become apparent to those skilled in the art upon examination of the description or may be learned by practice of the invention. The following examples are provided by way of illustration and are not intended to limit the present invention. Moreover, the present invention covers all possible combinations of the specific and preferred embodiments described herein.