阅读说明：本技术 奈非那韦作为冠状病毒广谱抑制剂的新用途 (New application of nelfinavir as coronavirus broad-spectrum inhibitor ) 是由 徐欢 童贻刚 范华昊 宋立华 周美玲 安小平 葛琳 刘艳玲 洪碧霞 翟丽丽 秦宏 于 2020-06-11 设计创作，主要内容包括：本发明公布了奈非那韦的新用途,奈非那韦可作为冠状病毒的广谱抑制剂用于治疗2019新型冠状病毒感染,严重急性呼吸综合症(SARS),中东呼吸综合症(MERS)以及人冠状病毒OC43(HCoV-OC43)引发的普通感冒。奈非那韦可以结合冠状病毒的主蛋白酶(3CL pro),还可以结合冠状病毒刺突蛋白S1,既能够阻断病毒进入细胞,又能够抑制病毒复制,是罕见的新冠病毒的双靶点抑制剂。作为老药新用,奈非那韦的安全性没有问题,因此可以应用于临床。(The invention discloses a new application of nelfinavir, which can be used as a broad-spectrum inhibitor of coronavirus for treating 2019 novel coronavirus infection, Severe Acute Respiratory Syndrome (SARS), Middle East Respiratory Syndrome (MERS) and common cold caused by human coronavirus OC43(HCoV-OC 43). Nelfinavir can bind to the main protease (3CL pro) of coronavirus and can also bind to the coronavirus spike protein S1, so that the nelfinavir can block the virus from entering cells and inhibit the virus from replicating, and is a rare double-target inhibitor of new coronavirus. The nelfinavir is used as an old medicine, has no problem in safety, and can be clinically applied.)

1. Use of nelfinavir in the preparation of a medicament for the prevention and treatment of coronavirus infection.

2. Use according to claim 1, characterized in that: the coronavirus comprises 2019 novel coronavirus COVID-19, severe acute respiratory syndrome SARS virus, middle east respiratory syndrome MERS virus, common cold virus HCoV-OC43, human coronavirus NL63, human coronavirus 229E and human coronavirus HKU 1.

3. Use according to claim 1, characterized in that: the coronavirus includes 2019 novel coronavirus COVID-19, severe acute respiratory syndrome SARS virus and middle east respiratory syndrome MERS virus.

4. Use according to claim 1, characterized in that: the coronavirus is a 2019 novel coronavirus COVID-19.

5. Use according to any one of claims 1 to 4, characterized in that: the coronavirus infection is coronavirus pneumonia or common cold.

6. Use according to any one of claims 1-2, characterized in that: the coronavirus infection comprises 2019 novel coronavirus COVID-19 pneumonia, severe acute respiratory syndrome SARS, middle east respiratory syndrome MERS, common cold, human coronavirus NL63 pneumonia, human coronavirus 229E pneumonia, and human coronavirus HKU1 pneumonia.

7. Use according to any one of claims 1 to 3, characterized in that: the coronavirus infection comprises 2019 novel coronavirus COVID-19 pneumonia, severe acute respiratory syndrome SARS and middle east respiratory syndrome MERS.

8. Use according to any one of claims 1 to 4, characterized in that: the coronavirus infection is 2019 novel coronavirus COVID-19 pneumonia.

9. Use according to any one of claims 1 to 4, characterized in that: rutin can bind to the spike protein S1 of coronavirus and coronavirus main protease 3 CLpro.

10. Use according to any one of claims 1 to 4, characterized in that: rutin can combine with the spike protein S1 of 2019 novel coronavirus COVID-19 and coronavirus main protease 3 CLpro.

Technical Field

The invention belongs to the field of medicines, relates to a new application of nelfinavir, and particularly relates to an application of nelfinavir in preventing or treating coronavirus infection.

Background

Highly pathogenic coronavirus infection has become a public health concern over the last decade. Severe acute respiratory syndrome (SARS, 2002-2004), middle east respiratory syndrome (MERS, 2012-to-date), 2019 novel coronaviruses (2019-nCoV, COVID-19), each of which has a tremendous impact on human health and economic development.

Because there are no effective drugs and vaccines, the research and development of new drugs for new coronavirus is of great significance, and in the war without smoke, a plurality of scientific research institutions and pharmaceutical companies around the world are dedicated to research and develop new coronavirus vaccines and therapeutic drugs. Therefore, the invention has great social and economic significance.

Nelfinavir, originally used in acquired immunodeficiency syndrome (aids) and HIV-1 infected patients. The product is a non-peptide HIV protease inhibitor, can be combined with active bond of HIV protease in a reversible manner to prevent HIV protease and influence the final formation of virus. The product has stronger effect than saquinavir, and is similar to indinavir and ritonavir.

Disclosure of Invention

The purpose of the present invention is to provide an effective inhibitor for coronaviruses including a 2019 novel coronavirus (COVID-19), which can prevent and treat infection with coronaviruses including a 2019 novel coronavirus. The invention provides a new application of nefinavir, which is an effective inhibitor of coronavirus including 2019 novel coronavirus, and an application of the nefinavir in preparation of a medicament for preventing or treating coronavirus infection.

The application is that the coronavirus comprises 2019 novel coronavirus (COVID-19), Severe Acute Respiratory Syndrome (SARS) virus, Middle East Respiratory Syndrome (MERS) virus, common cold human coronavirus OC43(HCoV-OC43), human coronavirus NL63(HCoV-NL63), human coronavirus 229E (HCoV-229E) and human coronavirus HKU1(HCoV-HKU 1).

The application, wherein the coronavirus is 2019 novel coronavirus (COVID-19).

The use wherein the coronavirus infection is coronavirus pneumonia or common cold.

The application, wherein the coronavirus infection comprises 2019 novel coronavirus COVID-19 pneumonia, severe acute respiratory syndrome SARS, middle east respiratory syndrome MERS, common cold, human coronavirus NL63 pneumonia, human coronavirus 229E pneumonia, and human coronavirus HKU1 pneumonia.

The use of (b), wherein the coronavirus infection is 2019 novel coronavirus pneumonia.

The inventor discovers a new application of nelfinavir through a great deal of research, wherein the nelfinavir can combine the spike protein S1 of 2019 novel coronavirus and coronavirus main protease (3CLpro) to interfere the cleavage of RNA virus precursor protein, thereby inhibiting virus replication. Nelfinavir at cellular level EC50 ═ 6.705 uM.

2019 the novel coronavirus enters into cell and recognizes receptor ACE2 by spike protein spike, and two key proteases involved in the proteolysis process of coronavirus are coronavirus main protease (3CLpro) and papain-like protease (PLpro), respectively. Therefore, small molecule inhibitors targeting both spike and 3Clpro proteins can be applied in therapy against novel coronaviruses.

The inventors have also found that nelfinavir binds equally well to the S1/3CL target protein of SARS and MERS. The 3CL protease is a key protease for catalyzing the cleavage of RNA virus precursor protein and has an important effect on the replication of the virus. Thus, nelfinavir can be applied in the treatment of individual subtype coronavirus infections.

The compounds of the present invention may be formulated into various suitable pharmaceutical preparation forms. Can be used alone, or mixed with medicinal adjuvants (such as excipient, diluent, etc.) to make into oral tablet, capsule, granule or syrup, or powder for injection or solution.

Compared with the prior art, the invention has the following technical effects:

the nelfinavir can inhibit coronavirus main protease (3CLpro) at a cellular level, obviously inhibit virus replication, and can be combined with a spike protein S1 of the coronavirus to block the virus from entering cells, so that the effect of treating coronavirus pneumonia infection and common cold is achieved, and particularly the infection of 2019 novel coronavirus, severe acute respiratory syndrome virus or middle east respiratory syndrome virus is involved.