阅读说明：本技术 苦味受体激动剂及其在预防和治疗SARS-CoV-2相关传染病中的应用 (Bitter taste receptor agonist and its application in preventing and treating SARS-CoV-2 related infectious disease ) 是由 李湘麒 张朝宝 任莉 刘连勇 顾明君 于 2020-03-23 设计创作，主要内容包括：本发明涉及苦味受体激动剂及其在预防和治疗SARS-CoV-2相关传染病中的应用。具体而言,本发明涉及苦味受体激动剂作为2019新型冠状病毒(SARS-CoV-2)抑制剂在制备治疗和/或预防、缓解由2019新型冠状病毒感染引起的呼吸道感染、肺炎等相关疾病的药物中的用途。(The present invention relates to bitter receptor agonists and their use in the prevention and treatment of SARS-CoV-2 related infectious disease. Specifically, the invention relates to application of a bitter receptor agonist as a 2019 novel coronavirus (SARS-CoV-2) inhibitor in preparation of a medicine for treating and/or preventing and relieving related diseases such as respiratory tract infection, pneumonia and the like caused by 2019 novel coronavirus infection.)

1. Use of an active ingredient or a formulation containing said active ingredient, wherein said active ingredient is selected from the group consisting of:

(Z1) any one of active ingredients (bitter receptor agonists) from B1 to B45, or a pharmaceutically acceptable salt or extract thereof;

(B1) diphenylpiperidinebutanol;

(B2) quinine;

(B3) chlorpheniramine maleate;

(B4) benzoguanamine amide;

(B5) (ii) a glycoside chrysanthemum;

(B6) georgenin;

(B7) chloramphenicol;

(B8) rhamnus davurica pall essence;

(B9) kudu ning;

(B10) a quassin;

(B11) azathioprine;

(B12) mugwort ene lactone;

(B13) papaverine;

(B14) caffeine;

(B15) yohimbine;

(B16) chloroquine;

(B17) camphor;

(B18) dapsone;

(B19) strychnine;

(B20) dextromethorphan;

(B21) haloperidol;

(B22) strychnine;

(B23) coumarin;

(B24) cucurbitacin B;

(B25) (-) -a-soil johns;

(B26) benzoin;

(B27) famotidine;

(B28) cucurbitacin E;

(B29) a cycloheximide;

(B30) erythromycin;

(B31) diphenylthiourea;

(B32) colchicine;

(B33) sodium benzoate;

(B34) diphenhydramine;

(B35) myo-calming;

(B36) noscapine;

(B37) a benzamide;

(B38) chlorhexidine;

(B39) divinyl sulfoxide;

(B40) flufenamic acid;

(B41) 4-hydroxyanisole;

(B42) hydrocortisone;

(B43) o-tolylhydramine;

(B44) tower imputed B;

(B45) artemisinin;

(Z2) any combination of the above active ingredients B1 to B45;

and said active ingredient or a formulation containing said active ingredient is used for the preparation of (a) an inhibitor for inhibiting coronavirus; and/or (b) a medicament for the treatment and/or prevention, amelioration of a related disease caused by a coronavirus infection.

2. The use of claim 1, wherein the coronavirus is selected from the group consisting of: coronavirus infecting human, Severe acute respiratory syndrome coronavirus SARS-CoV (SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), Middle East respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus MERS-CoV), or common cold-causing coronavirus; the common cold-causing coronavirus is preferably Human coronavirus OC43(Human coronavirus OC43), Human coronavirus 229E (Human coronavirus 229E), Human coronavirus NL63(Human coronavirus NL63), and Human coronavirus HKUL (Human coronavirus HKUL).

3. The use according to claim 1, wherein the active ingredient is used for the preparation of (a)2019 a novel coronavirus (SARS-CoV-2) inhibitor; and/or (b) a medicament for treating and/or preventing, alleviating related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.

4. The use of claim 1, wherein the related disease caused by the 2019 novel coronavirus infection is selected from the group consisting of: respiratory infections, pneumonia and its complications, or combinations thereof.

5. The use according to claim 1, wherein the active ingredient is selected from the group consisting of: selected from any one of active ingredients B1-B15 and B20-40, or pharmaceutically acceptable salt or extract thereof.

6. The use according to claim 1, wherein the active ingredient is selected from the group consisting of: difenidol, quinine, chloroquine, artemisinin, chlorpheniramine, yohimbine, dextromethorphan, or combinations thereof.

7. The use according to claim 1, wherein said formulation containing said active ingredient comprises: oral and non-oral formulations.

8. A pharmaceutical composition, comprising:

(a) a first active ingredient selected from any one of B1-B45 (bitter taste receptor agonist), or a pharmaceutically acceptable salt or extract thereof;

and (b) a pharmaceutically acceptable carrier.

9. The pharmaceutical composition of claim 8, wherein the pharmaceutical composition comprises:

(a1) a first active ingredient selected from the group consisting of: any one of active ingredients (bitter receptor agonists) of B1 to B45, or a pharmaceutically acceptable salt or extract thereof;

(a2) a second active ingredient selected from the group consisting of: inhibitors of RNA replicase (e.g., Remdesivir (Rudexilvir or GS-5734)); lopinavir (Lopinavir), Ritonavir (Ritonavir); chloroquine (Chloroquine, Sigma-C6628), hydroxychloroquine, or a combination thereof; and

and (b) a pharmaceutically acceptable carrier.

10. Use of a pharmaceutical composition according to claim 8 or 9 for the preparation of (a) an inhibitor for inhibiting coronavirus; and/or (b) a medicament for the treatment and/or prevention, amelioration of a related disease caused by a coronavirus infection.

Technical Field

The invention relates to the field of medicine, in particular to a bitter receptor agonist and application thereof in preventing and treating SARS-CoV-2 related infectious diseases.

Background

Diseases caused by the novel coronavirus SARS-CoV-2 (also known as 2019-nCoV) cause systemic symptoms, are infectious, and become a serious disease of global outbreak (2-4). Coronavirus diseases are formally named COVID-19 by the World Health Organization (WHO). International travel promotes the exacerbation of dissemination (5). 30/1/2020, the world health organization announces SARS-CoV-2 as an emergent Public Health Event (PHEIC) of international concern. On 23 days 3/2020, there are already over 23 million cases. Outbreaks continue and are now considered to have been declared a pandemic by the WHO. The morbidity, mortality and dissemination of this new coronavirus has not yet been resolved (6, 7). In the absence of effective antiviral therapy, mandatory measures must be taken to prevent interpersonal transmission. However, for those severe patients, the chances of death are high.

Despite some suggestions, no specific drug has cured this catastrophic disease (8). Some new drugs are reported to be undergoing clinical trials SARS-CoV-2(28), but are still in the early stages of development. There is an urgent need to find effective drugs to combat this disease.

Disclosure of Invention

The purpose of the present invention is to provide a pharmaceutically active ingredient which is effective for the prevention and/or treatment of coronavirus such as SARS-CoV-2.

Specifically, the invention provides bitter taste receptor agonists and their use in the prevention and/or treatment of SARS-CoV-2 related infectious diseases.

In a first aspect of the invention there is provided the use of an active ingredient or a formulation containing said active ingredient, said active ingredient being selected from the group consisting of:

(Z1) any one of active ingredients (bitter receptor agonists) from B1 to B45, or a pharmaceutically acceptable salt or extract thereof;

(B1) diphenylpiperidinebutanol;

(B2) quinine;

(B3) chlorpheniramine maleate;

(B4) benzoguanamine amide;

(B5) (ii) a glycoside chrysanthemum;

(B6) georgenin;

(B7) chloramphenicol;

(B8) rhamnus davurica pall essence;

(B9) kudu ning;

(B10) a quassin;

(B11) azathioprine;

(B12) mugwort ene lactone;

(B13) papaverine;

(B14) caffeine;

(B15) yohimbine;

(B16) chloroquine;

(B17) camphor;

(B18) dapsone;

(B19) strychnine;

(B20) dextromethorphan;

(B21) haloperidol;

(B22) strychnine;

(B23) coumarin;

(B24) cucurbitacin B;

(B25) (-) -a-soil johns;

(B26) benzoin;

(B27) famotidine;

(B28) cucurbitacin E;

(B29) a cycloheximide;

(B30) erythromycin;

(B31) diphenylthiourea;

(B32) colchicine;

(B33) sodium benzoate;

(B34) diphenhydramine;

(B35) myo-calming;

(B36) noscapine;

(B37) a benzamide;

(B38) chlorhexidine;

(B39) divinyl sulfoxide;

(B40) flufenamic acid;

(B41) 4-hydroxyanisole;

(B42) hydrocortisone;

(B43) o-tolylhydramine;

(B44) tower imputed B;

(B45) artemisinin;

(Z2) any combination of the above active ingredients B1 to B45;

and said active ingredient or a formulation containing said active ingredient is used for the preparation of (a) an inhibitor for inhibiting coronavirus; and/or (b) a medicament for the treatment and/or prevention, amelioration of a related disease caused by a coronavirus infection.

In another preferred embodiment, the medicament further comprises one or more additional active ingredients selected from the group consisting of:

(Y1) a Chinese medicinal preparation for inhibiting virus or an active ingredient thereof;

(Y2) RNA replicase inhibitors (e.g., Remdesivir (redevir or GS-5734));

(Y3) Lopinavir (Lopinavir), Ritonavir (Ritonavir);

(Y4) Chloroquine (Chloroquine, Sigma-C6628), or a pharmaceutically acceptable salt thereof;

(Y5) hydroxychloroquine, or a pharmaceutically acceptable salt thereof.

In another preferred embodiment, the bitter taste receptor is a type 2 taste receptor.

In another preferred embodiment, the coronavirus is selected from the group consisting of: coronavirus infecting human, Severe acute respiratory syndrome coronavirus SARS-CoV (SARS-CoV), 2019 novel coronavirus (2019-nCoV or SARS-CoV-2), Middle East respiratory syndrome coronavirus MERS-CoV (Middle East respiratory syndrome coronavirus MERS-CoV), or common cold-causing coronavirus; the common cold-causing coronavirus is preferably Human coronavirus OC43(Human coronavirus OC43), Human coronavirus 229E (Human coronavirus 229E), Human coronavirus NL63(Human coronavirus NL63), and Human coronavirus HKUL (Human coronavirus HKUL).

In another preferred embodiment, the coronavirus is selected from the group consisting of: an alpha genus coronavirus, a beta genus coronavirus, or a combination thereof.

In another preferred embodiment, the coronavirus is selected from the group consisting of: HCoV-229E, HCoV-OC43, SARS-CoV, HCoV-NL63, HCoV-HKU1, MERS-CoV, SARS-CoV-2, or a combination thereof.

In another preferred embodiment, the coronavirus is selected from the group consisting of: 2019 novel coronavirus (SARS-CoV-2), SARS virus, MERS virus, or a combination thereof.

In another preferred embodiment, the active ingredient is used in the preparation of (a)2019 a novel coronavirus (SARS-CoV-2) inhibitor; and/or (b) a medicament for treating and/or preventing, alleviating related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection.

In another preferred example, the related disease caused by the 2019 novel coronavirus infection is selected from the group consisting of: respiratory infections, pneumonia and its complications, or combinations thereof.

In another preferred example, the related diseases caused by 2019 novel coronavirus (SARS-CoV-2) infection comprise novel coronavirus pneumonia (Corona Virus Disease 2019, COVID-19).

In another preferred embodiment, the active ingredient is selected from the group consisting of: selected from any one of active ingredients B1-B15 and B20-40, or pharmaceutically acceptable salt or extract thereof.

In another preferred embodiment, the active ingredient is selected from the group consisting of: difenidol, quinine, chloroquine, artemisinin, chlorpheniramine, yohimbine, dextromethorphan, or combinations thereof.

In another preferred embodiment, the formulation containing the active ingredient comprises: oral and non-oral formulations.

In another preferred embodiment, the formulation comprises: powder, granule, capsule, injection, tincture, oral liquid, tablet, buccal tablet, or dripping pill.

In another preferred embodiment, the non-oral administration dosage form is injection or injection.

In a second aspect, the present invention provides a pharmaceutical composition comprising:

(a) a first active ingredient selected from any one of B1-B45 (bitter taste receptor agonist), or a pharmaceutically acceptable salt or extract thereof;

and (b) a pharmaceutically acceptable carrier.

In another preferred embodiment, the pharmaceutical composition is a pharmaceutical composition for inhibiting coronavirus.

In another preferred embodiment, the pharmaceutical composition does not contain any active ingredient (e.g., antiviral active ingredient) other than any active ingredient (bitter receptor agonist) selected from B1-B45, or a pharmaceutically acceptable salt or extract thereof.

In another preferred embodiment, the pharmaceutical composition comprises:

(a1) a first active ingredient selected from the group consisting of: any one of active ingredients (bitter receptor agonists) of B1 to B45, or a pharmaceutically acceptable salt or extract thereof;

(a2) a second active ingredient selected from the group consisting of: inhibitors of RNA replicase (e.g., Remdesivir (Rudexilvir or GS-5734)); lopinavir (Lopinavir), Ritonavir (Ritonavir); chloroquine (Chloroquine, Sigma-C6628), hydroxychloroquine, or a combination thereof; and

and (b) a pharmaceutically acceptable carrier.

In a third aspect of the invention, there is provided the use of a pharmaceutical composition according to the second aspect of the invention in the preparation of a medicament for (a) inhibiting a coronavirus; and/or (b) a medicament for the treatment and/or prevention, amelioration of a related disease caused by a coronavirus infection.

It is to be understood that within the scope of the present invention, the above-described features of the present invention and those specifically described below (e.g., in the examples) may be combined with each other to form new or preferred embodiments. Not to be reiterated herein, but to the extent of space.

Drawings

FIG. 1 shows the main functional pathway of TAS2R10, which was determined by the Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis. Gene enrichment analysis for negative co-expression with TAS2R10 was performed based on 60,000 Affymetrix expression arrays and 5,000 datasets from cancer genomic maps (TCGA). TAS2R10 was shown to play a role in the prevention of several human diseases. TAS2R10, is bitter taste receptor member 10.

FIG. 2 shows additional infectious diseases determined by KEGG analysis to be regulated by TAS2R 10. Enrichment analysis of genes co-expressed negatively with TAS2R10 was performed based on 60000 Affymetrix expression arrays and 5000 TCGA datasets.

Figure 3 shows the cytokine storm associated pathway regulated by TAS2R10 as determined by KEGG analysis. Enrichment analysis of genes co-expressed negatively with TAS2R10 was performed based on 60000 Affymetrix expression arrays and 5000 TCGA datasets. TAS2R10 controls cytokine storms by regulating multiple pathways.

Detailed Description

The present inventors have conducted extensive and intensive studies and, for the first time, have unexpectedly developed a bitter taste receptor agonist which is effective for the treatment and/or prevention of 2019 of a novel coronavirus (SARS-CoV-2) and the like. Experiments show that the active molecule (bitter receptor agonist) or the pharmaceutically acceptable salt thereof can be used for efficiently resisting the infection of the 2019 novel coronavirus (SARS-CoV-2) and other coronaviruses. The present invention has been completed based on this finding.

Specifically, the present inventors performed a negative co-expression analysis using large data from 60,000 Affymetrix expression chips and 5,000 TCGA datasets to determine the function of TAS2R10, TAS2R10 being activated by a large amount of bitter substances. Exciting, the inventors found that the main function of TAS2R10 is to control infectious diseases caused by bacteria, viruses and parasites, suggesting that TAS2R10 is a key gene in host defense pathways. To rapidly guide the clinical treatment of SARS-CoV-2, the inventors searched the existing drug library for agonists of TAS2 Rs. The present inventors have identified several inexpensive, available and safe drugs, such as difenidol, quinine, chloroquine, artemisinin, chlorpheniramine, yohimbine and dextromethorphan, which are likely to be directed against the most common symptoms of SARS-CoV-2. The present inventors suggest that the existing cocktail-like formulations of bitter drugs may help physicians fight this catastrophic disease and suggest that the public drinks or eats bitter substances, such as coffee, tea or bitter herbs, to reduce the risk of infection.

Term(s) for

As used herein, "an active compound of the present invention", "an active compound of the present invention inhibiting coronavirus", which are used interchangeably, refer to a compound having an excellent coronavirus inhibitory activity, or a combination thereof.

As used herein, "medicinal material of the present invention" refers to a Chinese medicinal material containing the active compound of the present invention.

As used herein, "extract of medicinal material of the present invention" or "extract of the present invention" refers to an extract obtained by extraction of a Chinese medicinal material or corresponding plant and containing one or more active compounds of the present invention.

As used herein, "a formulation of the invention" refers to a formulation containing an active compound of the invention, including both traditional Chinese medicine formulations and non-traditional Chinese medicine formulations.

As used herein, the term "comprising" or variations thereof, such as "comprises" or "comprising," etc., will be understood to imply the inclusion of stated elements or components but not the exclusion of any other elements or components.

Abbreviations

TAS 2R: type 2 taste receptors;

HDT: host-directed therapy.

WHO: the world health organization.

PHEIC: a sudden public health event of international concern.

GPCR: g protein coupled receptors.

RMA: robust multi-chip averaging.

AMPs: an antimicrobial peptide.

TLR: toll-like receptors.

TNF- α: tumor necrosis factor alpha.

KEGG: kyoto gene and genome encyclopedia.

TCGA: atlas of cancer genomes.

Coronavirus (coronavirus)

Coronaviruses (CoV) belong to the family of the Nidovirales (Nidovirales) Coronaviridae (Coronaviridae), a enveloped positive-strand RNA virus, a subfamily of which contains four genera, alpha, beta, delta and gamma.

Among the coronaviruses currently known to infect humans, HCoV-229E and HCoV-NL63 belong to the genus alpha coronavirus, and HCoV-OC43, SARS-CoV, HCoV-HKU1, MERS-CoV and SARS-CoV-2 are all the genus beta coronavirus.

Highly pathogenic coronaviruses SARS-CoV and MERS-CoV, which outbreak in 2003 and 2012, respectively, both belong to the genus beta coronavirus. The novel coronavirus (SARS-CoV-2) which is outbreak in 2019 and has 80% similarity with SARS-CoV and 40% similarity with MERS-CoV, and also belongs to the beta genus coronavirus.

The genome of the virus is a single-strand positive-strand RNA, is one of RNA viruses with the largest genome, and codes comprise replicase, spike protein, envelope protein, nucleocapsid protein and the like. In the initial stage of viral replication, the genome is translated into two peptide chains of up to several thousand amino acids, the precursor Polyprotein (Polyprotein), which is subsequently cleaved by proteases to yield nonstructural proteins (e.g., RNA polymerase and helicase) and structural proteins (e.g., spike protein) and accessory proteins.

Active Compounds and active ingredients of the invention

The present invention provides an active ingredient which is effective in inhibiting the replication of a novel coronavirus (SARS-CoV-2) of 2019. The active ingredient is selected from the group consisting of:

(Z1) is selected from any one of active ingredients B1-B45, or a pharmaceutically acceptable salt or extract thereof;

(Z2) any combination of the above active ingredients B1 to B45 (including any combination of two or more of the above active ingredients Z1).

Experiments show that the active compound of the invention can effectively inhibit 2019 novel coronavirus (SARS-CoV-2) so as to prevent, treat and/or relieve SARS-CoV-2 related diseases.

As used herein, "an active compound of the present invention", "an active compound of the present invention inhibiting coronavirus", which are used interchangeably, refer to a compound having an excellent coronavirus inhibitory activity, which is any one of active ingredients B1 to B45, or a combination thereof.

It is to be understood that the active ingredients of the present invention include the coronavirus-inhibiting active compounds of the present invention, or a pharmaceutically acceptable salt, enantiomer, diastereomer or racemate thereof, or a prodrug thereof. It is to be understood that the active ingredients of the present invention also include crystalline, amorphous, deuterated, solvates, hydrates, and the like forms of the active compounds of the present invention.

The "pharmaceutically acceptable salts" are conventional non-toxic salts formed by the reaction of the active compounds of the present invention with inorganic or organic acids. For example, conventional non-toxic salts can be prepared by reacting the active compounds of the present invention with inorganic acids including hydrochloric acid, hydrobromic acid, sulfuric acid, nitric acid, sulfamic acid, phosphoric acid and the like, or organic acids including citric acid, tartaric acid, lactic acid, pyruvic acid, acetic acid, benzenesulfonic acid, p-toluenesulfonic acid, methanesulfonic acid, naphthalenesulfonic acid, ethanesulfonic acid, naphthalenedisulfonic acid, maleic acid, malic acid, malonic acid, fumaric acid, succinic acid, propionic acid, oxalic acid, trifluoroacetic acid, stearic acid, pamoic acid, hydroxymaleic acid, phenylacetic acid, benzoic acid, salicylic acid, glutamic acid, ascorbic acid, p-aminobenzenesulfonic acid, 2-acetoxybenzoic acid, isethionic acid and the like; or sodium, potassium, calcium, aluminum or ammonium salts of the active compounds of the invention which are esterified with propionic acid, oxalic acid, malonic acid, succinic acid, fumaric acid, maleic acid, lactic acid, malic acid, tartaric acid, citric acid, aspartic acid or glutamic acid and then with an inorganic base; or the methylamine, ethylamine or ethanolamine salt of an active compound of the invention with an organic base; or the corresponding inorganic acid salt formed by the active compound of the invention and lysine, arginine and ornithine after forming ester and then hydrochloric acid, hydrobromic acid, hydrofluoric acid, sulfuric acid, nitric acid or phosphoric acid, or the corresponding organic acid salt formed by the active compound of the invention and formic acid, acetic acid, picric acid, methanesulfonic acid or ethanesulfonic acid.

Furthermore, the active ingredients of the invention are particularly suitable for use in combination with other antiviral drugs. Representative other antiviral drugs include (but are not limited to): a reverse transcriptase inhibitor, a protease inhibitor, a co-receptor antagonist, a retroviral integrase inhibitor, a viral adsorption inhibitor, a specific viral transcription inhibitor, an antibody, or a combination thereof.

The active component of the present invention can regulate human immune system to inhibit the infection activity of SARS-CoV-2 and other new coronavirus. Therefore, when the active ingredient of the present invention is administered or administered prophylactically or therapeutically to a subject (e.g., human), the human immune system can be modulated by the action of the bitter receptor agonist, thereby inhibiting 2019 infection by the novel coronavirus (SARS-CoV-2), and achieving antiviral action.

Pharmaceutical composition and application

The invention also provides application of an active compound inhibiting the coronavirus, or a pharmaceutically acceptable salt, a prodrug, an extract or a mixture of one or more of medicinal materials thereof as an active ingredient in preparing a medicament for treating and/or preventing and relieving related diseases such as respiratory tract infection, pneumonia and the like caused by 2019 novel coronavirus infection.

The pharmaceutical composition provided by the present invention preferably contains 0.001-99 wt% of active ingredient, preferably 0.1-90 wt% or 1-50 wt% of active compound of the present invention as active ingredient, the rest being pharmaceutically acceptable carrier, diluent or solution or salt solution.

If necessary, one or more pharmaceutically acceptable carriers can be added into the medicine. The carrier comprises diluents, excipients, fillers, binders, wetting agents, disintegrants, absorption enhancers, surfactants, adsorption carriers, lubricants and the like which are conventional in the pharmaceutical field.

The compounds and pharmaceutical compositions provided herein may be in a variety of forms such as tablets, capsules, powders, syrups, solutions, suspensions and aerosols, and the like, and may be presented in suitable solid or liquid carriers or diluents and in suitable sterile devices for injection or instillation.

Various dosage forms of the pharmaceutical composition of the present invention can be prepared according to conventional preparation methods in the pharmaceutical field. The unit dose of the formulation generally comprises 0.05 to 400mg of active compound according to the invention, preferably 1 to 500mg of active compound according to the invention.

The compounds and pharmaceutical compositions of the present invention may be administered to mammals in the clinical setting, including humans and animals, by oral, nasal, dermal, pulmonary or gastrointestinal routes of administration. Most preferably oral. Most preferably, the daily dose is 0.01-400mg/kg body weight, and is administered once or in portions of 0.01-200mg/kg body weight. Regardless of the method of administration, the optimal dosage for an individual will depend on the particular treatment. Usually starting with a small dose and gradually increasing the dose until the most suitable dose is found.

The drug or inhibitor of the present invention can be administered by a variety of different means, e.g., by injection, spray, nasal drop, eye drop, osmotic, absorption, physical or chemical mediated methods, into the body such as muscle, intradermal, subcutaneous, intravenous, mucosal tissue; or mixed with other materials or encapsulated and introduced into body.

The main advantages of the invention include:

(a) the active compounds of the invention are all old medicines, have low toxic and side effects and good patent medicine property.

(b) The bitter receptor stimulant can effectively regulate the immunity of human body to prevent and/or treat SARS-CoV-2 virus, so as to achieve the effect of resisting SARS-CoV-2 and other coronavirus.

The invention will be further illustrated with reference to the following specific examples. It should be understood that these examples are for illustrative purposes only and are not intended to limit the scope of the present invention. The experimental procedures, in which specific conditions are not noted in the following examples, are generally carried out under conventional conditions or conditions recommended by the manufacturers. Unless otherwise indicated, percentages and parts are by weight.

Example 1: data collection and analysis

Gene expression data is retrieved from the EBI database and the combined CEL file is preprocessed using robust multi-chip average (RMA) normalization methods. The cutoff value for the standard deviation level was 0.25 to ensure high quality of data and capture significantly relevant transcriptome information.

The present inventors collected and pretreated 60,000 Affymetrix expression chips and 5,000 TCGA datasets. KEGG analysis was performed to enrich for the most significantly related signaling pathway. The genes with the highest negative correlation to TAS2R10 expression were analyzed for biological pathways. Pearson correlations between TAS2R10 probe and other probes were calculated and the p-value was an unmodified p-value. The q-value packet in R is used for multiple test corrections. Genes with q values below 0.05 were considered as significantly negative co-expressed genes for TAS2R 10. The measurement and statistical analysis of the relevant parameters is performed as previously described (25).

Drug screening

Bitter agonists and TAS2Rs were retrieved from published references in the NCBI database. Bitter agonists of TAS2R10 or other TAS2R members were analyzed based on available references. Reference is made primarily to 3 main research documents (19, 22, 23). The mechanism of action of the selected drug was retrieved from the DRUGBANK database.

Results

TAS2R10 inhibiting potential functions of infectious diseases caused by bacteria, viruses and parasites

Based on 60,000 Affymetrix expression arrays and 5,000 TCGA datasets, the inventors performed KEGG analysis to identify diseases in which TAS2R10 might be involved (fig. 1).

Through enrichment analysis, the present inventors found that, in addition to various cancers and neurodegenerative diseases, significantly related items were focused on infectious diseases caused by bacteria, viruses and parasites. For infectious diseases, TAS2R10 may be involved in the control of legionnaires' disease, pertussis, toxoplasmosis, Shigellasis, tuberculosis and HTLV-1 infection. In addition to these important items, TAS2R10 may control other infectious diseases (fig. 2), such as pathogenic escherichia coli infections, epithelial bacterial invasion, salmonella infections, vibrio cholerae infections, epithelial cell signaling in helicobacter pylori infections, epstein-barr virus infections, hepatitis c, hepatitis b, viral diseases, herpes simplex infections, influenza a, measles, viral myocarditis, chagas disease (trypanosomiasis americana), amebiasis and leishmaniasis. These results suggest that TAS2R10 may be a key regulatory factor in host response to a variety of infectious diseases.

Cytokine storm is a very important event and is a significant cause of death in patients with coronavirus infection. Thus, inhibition of an overactive immune response is a key element in preventing cytokine storms. Indeed, the inventors have discovered that TAS2R10 may have this function because it can modulate natural killer cell-mediated cytotoxicity, chemokine signaling pathways, T cell receptor signaling pathways, TNF signaling pathways, B cell receptor signaling pathways, Fc γ R-mediated phagocytosis, Fc epsilon RI signaling pathways, leukocyte transendothelial migration, antigen processing and presentation, and NF- κ B signaling pathway (fig. 3). A cytokine storm is initiated by the human immune system to attack viruses, but it also causes damage to human cells. By KEGG analysis, TAS2R10 was found to modulate autoimmune diseases such as systemic lupus erythematosus and rheumatoid arthritis (figure 3).

Acting as TAS2R agonist, can be used as clinical medicine for treating infectious diseases

From the above analysis, the inventors concluded that TA2R10 may be very important for controlling infectious diseases caused by bacteria, viruses and parasites. Thus, TAS2R10 agonists are potential candidates for the treatment of infectious diseases. The present inventors searched available references relating to TAS2R10 and other TAS2R members to identify clinical drugs that could activate bitter taste receptors. The inventors also analyzed the clinical application of these drugs in DRUGBANK. The present inventors have found a number of drugs that can activate TAS 2R.

Interestingly, many drugs can stimulate multiple TAS2R members. Considering gene expression, these drugs may have a strong effect on the resistance against infectious diseases in clinical applications. The first drug that activated the most abundant TAS2R members was diphenylpiperidinol, which stimulates 15 members of the TAS2R family. Clinically, diphenylpiperidinebutanol is an antiemetic, and is commonly used to treat motion sickness or seasickness. The second is quinine, which stimulates 9 members of TAS2R for the treatment of malaria. The third and fourth drugs are chlorpheniramine and benzalkonium benzoate. Chlorpheniramine is an antihistamine used to relieve allergic symptoms, while benzalkonium benzoate is used as an antifeedant. Followed by chloramphenicol (antibiotic), azathioprine (immunosuppressant), papaverine (antispasmodic), narcotic caffeine, yohimbine (a commonly used health product for men), chloroquine for the treatment of malaria, dapsone (antibacterial agent), dextromethorphan (antitussive), haloperidol (antipsychotic), famotidine (gastric acid inhibitor) and erythromycin (antibiotic). There are also some drug receptors that are only TAS2R14 or TAS2R 46. (all results are summarized in Table 1)

TABLE 1 human TAS2R10, TAS2R14 and TAS2R46 agonist drugs

Note that: all drugs are approved unless otherwise indicated. The drug was retrieved in DRUGBANK. See materials and methods for the main references for TAS2R member responses.

1) Wi indicates retired. Diphenylpiperidine butanol is an antiemetic, but an excess may cause serious toxicity to children.

2) In means investigational. Callistephora has been used in clinical studies to study the diagnosis of allergic contact dermatitis, but its efficacy has not been demonstrated in clinical applications. Benzoic acid is a fungistatic compound that is widely used as a food preservative and possibly as an adjunct therapy in schizophrenia. Diphenhydramine is widely used for the treatment of seasonal allergies, insect bites and rashes, and also has antiemetic, antitussive, hypnotic and antiparkinson properties.

3) No indicates No proof. Benzalkonium benzoate is used as an antifeedant and therefore may not be suitable for swallowing. It has also not been proven to be a drug in DRUGBANK and has potentially significant health risks.

4) Ve denotes veterinary verification. Chlorhexidine is a broad spectrum antibacterial biguanide used as a topical antiseptic in dental practice for the treatment of inflammatory dental conditions caused by microorganisms. Hydrocortisone is a glucocorticoid secreted by the adrenal cortex and is used for the treatment of immune, inflammatory and neoplastic diseases.

5) Benzoin is an FDA approved color colorant for fruit and vegetable marking.

6) Colchicine has been approved for the treatment of exacerbations of Familial Mediterranean Fever (FMF), a hereditary spontaneous inflammation.

7) Yohimbine has been used as a mydriatic and to treat impotence. It is also said to be a yang-invigorating drug.

8) Artemisinin is also a bitter tasting substance, but no bitter taste receptor activated by it has been reported. Of particular interest, artemisinin has a potent inhibitory effect on viruses, protozoa, helminths and fungi, and can inhibit infection, cancer and inflammation.

Discussion of the related Art

The current COVID-19 outbreak caused by SARS-CoV-2 results in over 7,000 deaths (1). There is an urgent need for inexpensive, available, safe and effective drugs to treat SARS-CoV-2 infection. HDT is suggested to help fight SARS-CoV-2 infection (9). TAS2R plays an important role in host defense mechanisms (15). Here, the inventors performed a large data analysis of the 60000 multiple data sets for TAS2R10 (which was activated by one third of the bitter substances tested) (19). Exciting results were obtained by negative gene co-expression analysis. Specifically, the inventors found that TAS2R10 is mainly involved in controlling various infectious diseases caused by bacteria, viruses and parasites, in addition to various cancers (fig. 1 and 2). This suggests that TAS2R10 may be a key gene in the host defense pathway. Previous observations have shown that their anti-cancer activity and modulation of smooth muscle relaxation are consistent with the results of the present inventors (20, 21). Other studies have shown that TAS2Rs can activate airway epithelial cells to secrete large amounts of antimicrobial peptides (AMPs), including β -defensins 1 and 2, a process that relies on the calcium signaling pathway (26-28). In addition, AMPs stimulated by TAS2Rs secreted very rapidly (approximately 5 minutes), but in response to Tol-like receptor (TLR) stimulation, an increase in AMP was observed over several hours (26). TAS2Rs also upregulates AMPs expression to reduce periodontitis (29). TAS2R38 is stimulated by acyl homoserine lactones and gram-negative quorum sensing molecules, which subsequently activate the nitric oxide-dependent innate immune response (16). The clustered cells, one of the intestinal epithelial cells, stimulate TAS2R to trigger a type 2 immune response upon sensing of worms (17). In addition, some genes essential for bitter taste perception, such as α -gustducin and Trpm5, are also important for initiating a type 2 immune response (30, 31). Human lymphocytes also directly express TAS2R (32). These reports are consistent with the inventors' results. Taken together, these findings suggest that TAS2Rs may strongly modulate innate immunity in humans and trigger host defenses to control infection (15). Recently, the world health organization scientist analyzed all currently available information about COVID-19 and found that SARS-CoV-2 replicates very rapidly in the upper respiratory tract, similar to the traditional human coronavirus (which are the main cause of the common cold in winter). Therefore, the upper respiratory tract is the most important key point in combating this fatal disease. AMPs can block the interaction between the virus and its receptor (33). Thus, the present inventors believe that the use of drugs to activate bitter receptors is an effective method of preventing the efficient replication of lethal viruses in the upper respiratory tract.

While the inventors sought clinical drugs that act as agonists of TAS2R (19, 22, 23), the inventors discovered a number of bitter drugs that have been shown to treat different diseases in clinical applications registered from DRUGBANK (table 1).

Unexpectedly, the first drug with the highest number of members of the responsive TAS2R was diphenylpiperidinol, an antiemetic agent used primarily in meniere's and labyrinthine patients to treat vomiting and vertigo (34). It is considered a relatively safe drug to control gastrointestinal discomfort (e.g. carsickness or seasickness). However, overdosing may cause serious toxicity to children (35).

The second drug, quinine, is commonly used to treat malaria. Quinine is also a mild antipyretic analgesic and still useful in the treatment of babesiosis and certain muscle diseases (36).

The third is chlorpheniramine, a histamine H1 receptor antagonist, commonly used to alleviate symptoms associated with anaphylaxis, pollinosis, rhinitis, urticaria and asthma (37).

Next follows chloramphenicol, an antibiotic used for the treatment of cholera and for the treatment of bacterial conjunctivitis in eye drops or ointments (36).

Although azathioprine is associated with certain adverse events (38), it is used in the treatment of inflammatory diseases, such as rheumatoid arthritis, and as an immunosuppressant in kidney transplantation.

Papaverine is a safe, direct-acting smooth muscle relaxant, useful in the treatment of impotence and as a vasodilator, especially for cerebral vasodilators (39).

Caffeine is useful in the prevention and treatment of neonatal apnea and bronchopulmonary dysplasia (40).

Interestingly, yohimbine is a male health product purportedly useful as an aphrodisiac and for strengthening muscles (41).

Chloroquine is an antimalarial agent used for the treatment of rheumatoid arthritis, systemic lupus erythematosus and amoeba liver abscess (42).

Camphor is used topically as an antipruritic and anti-infective agent, but may cause serious poisoning in children (43).

Dapsone is used primarily against mycobacterium leprae and in the treatment of malaria (44).

Dextromethorphan is widely used as an antitussive, recently also for neurological and psychiatric disorders (45).

These clinical applications registered in DRUGBANK are consistent with the inventors' proposed function of TAS2R in controlling various infectious diseases.

Cytokine storms are non-specific inflammatory responses caused by the hypersecretion of over 150 cytokines and chemical mediators by immune or non-immune defence cells and are characterized by rapid proliferation and high activation of T cells, macrophages and natural killer cells (46). This is a mechanism that the human immune system has to possess. Cytokine storms are also a critical event leading to death in patients with coronavirus infection (2, 47). Therefore, suppression of an overactive immune response is important to prevent cytokine storm (48). Indeed, the inventors have found that TAS2R10 may help prevent cytokine storm because it may modulate natural killer cell-mediated cytotoxicity, chemokine signaling pathways, T cell receptor signaling pathways, TNF signaling pathways, etc. (fig. 3).

Recent studies have confirmed the results of the present inventors that members 3, 4, 5, 9, 10, 14, 30, 39 and 40 of TAS2R are involved in inhibiting the production of macrophage cytokines such as TNF-a, CCL3 and CXCL8 in human lungs (49). Quinine, benzdenatonium, dapsone, colchicine, strychnine, chloroquine, erythromycin phenanthroline, ofloxacin and isoproterenol all work. In contrast, diphenylpiperidinebutanol had no effect, indicating that it may have a role in other organs. It has been reported that diphenybutanol, diphenhydramine and caffeine may accumulate in the reproductive organs (50), and that diphenybutanol has been shown to block voltage-gated Na (+) channels that can be associated with specific types of pain by inhibiting the expression of tumor necrosis factor TNF- α (51). Chlorpheniramine is used to relieve cough and upper respiratory symptoms caused by adult allergy or cold, and also to inhibit TNF production (52). Yohimbine, a selective alpha-adrenergic antagonist, reduces lipopolysaccharide-induced acute kidney injury in rats and inhibits cytokine production (53). Although there are no reports on its bitter taste receptor, artemisinin is widely used as an antimalarial and is also a bitter substance that can reduce pro-inflammatory cytokine production (54). Notably, artemisinin has a strong inhibitory effect on viruses, protozoa, helminths and fungi and is suggested to inhibit infection, cancer and inflammation due to its established safety record in millions of malaria patients (54, 55). In short, bitter drugs are good candidates for preventing cytokine storm.

Based on the above results, TAS2R and its agonists not only stimulate host defense, but also prevent hyperactive immune responses. This new HDT may be a viable option against COVID-19 related infectious diseases. Based on this, the present inventors provide the following suggestions for COVID-19.

1) To the general public: the results of the present inventors indicate that bitter drugs may not only be helpful against SARS-CoV-2, but may also be useful in the treatment of other infectious diseases. The safety is better than the remorse. To enhance body resistance and reduce the chance of infection, you are advised to drink coffee, tea, broadleaf holly leaf or lotus seed tea. The inventors also propose eating sow thistle and food such as bitter gourd, dandelion and chocolate to reduce the risk of infection (56, 57).

2) For mildly symptomatic patients and suspected cases: as a safety strategy, they should be given bitter anti-infective drugs. Infusion of bitter amino acids, such as L-valine, L-phenylalanine, L-tyrosine or L-tyrosine, may help to enhance body resistance (23, 58).

3) For patients with severe symptoms: bitter drugs can prevent cytokine storms, and therefore, these bitter drugs may be important for effective treatment of critically ill patients. They should be prescribed not only conventional anti-infective drugs, but also bitter drugs. The most common symptoms caused by SARS-CoV-2 are dyspnea, fever, cough and fatigue (2). Based on these clinical systemic symptoms, the inventors believe that a cocktail formulation of drugs may be helpful for these patients. By using lower clinical doses of each drug, the respective adverse side effects are reduced. For example, diphenylpiperidinebutanol is used for gastrointestinal distress; quinine, chloroquine or artemisinin may help kill microorganisms; chlorpheniramine maleate inhibits immune response; yohimbine is used for improving muscle strength; dextromethorphan is used for preventing cough (table 1). For infants infected with SARS-CoV-2, caffeine may be a good choice. Notably, a recent report suggests that chloroquine, one of the drugs proposed by the present inventors, kills SARS-CoV-2(59) at the cellular level. Importantly, this result supports the results of the present inventors' studies. Of course, personalized medical management should be performed by a radiologist.

In order to find more therapeutic agents, the present inventors have focused on a particular family of G protein-coupled receptors (GPCRs), called bitter taste receptors (TAS2Rs), which play a crucial role in host defense pathways (12, 13). Originally, TAS2R, whose ligand was a bitter tasting substance, was thought to be expressed only on the tongue. However, recent studies have shown that they are widely expressed in extraoral tissues such as the central nervous system, respiratory tract, breast, heart, stomach and intestinal mucosa, bladder, pancreas, testis, etc. (14, 15). This suggests that TAS2R may have other functions in addition to bitter taste. In fact, they are suggested to be involved in appetite regulation, asthma treatment, regulation of gastrointestinal motility and control of innate immunity (13, 15-17). Based on the agonist profile, TAS2Rs can be divided into broad, narrow and intermediate profile receptors (18). TAS2R10 is one of three widely regulated receptors, recognizing about one third of the bitter tasting substances tested to date (19). Therefore, it can greatly improve the bitter recognition ability of human body and has wide influence on human body. Despite several functional studies (20, 21), the detailed function of TAS2R10 is not fully understood.

Thus, the inventors believe that TAS2R10 is a useful model for identifying bitter receptor agonist function. Since the inventors hypothesized that bitter agonists might be helpful in treating covi-19, the inventors performed a negative co-expression analysis using 60,000 Affymetrix expression chips and 5,000 TCGA datasets for large data. Surprisingly, the results are consistent with the inventors' predictions. The present inventors have found that the primary function of TAS2R10 is related to the control of infectious diseases caused by bacteria, viruses and parasites. However, it is not practical to develop new drugs based on TAS2R to address current emergencies. To guide the clinical treatment of COVID-19 immediately, the inventors searched the drug library for agonists of TAS2Rs (19, 22, 23). Members of the TAS2R family may have similar functions, so the inventors also investigated two additional drugs with numerous bitter taste agonists, including TAS2R14 and TAS2R46 (24). The present inventors identified a number of inexpensive, available and safe drugs that may provide physicians with a good choice against SARS-CoV-2. Furthermore, the inventors suggest that the general public may drink coffee or tea and consume sow thistle to reduce the risk of infection.

All documents referred to herein are incorporated by reference into this application as if each were individually incorporated by reference. Furthermore, it should be understood that various changes and modifications of the present invention can be made by those skilled in the art after reading the above teachings of the present invention, and these equivalents also fall within the scope of the present invention as defined by the appended claims.

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