Polypeptides capable of inhibiting human coronavirus infections in a broad spectrum manner, and applications thereof

Abstract

The present invention belongs to the field of biomedicine, and relates to polypeptides capable of inhibiting human coronavirus infections, particularly to polypeptides capable of inhibiting human coronavirus infections in a broad spectrum manner, and applications thereof. According to the present invention, the polypeptides capable of providing broad spectrum inhibition effects for infections caused by more than 2 human coronaviruses are provided based on the conservation property of the S2 region of a coronavirus S protein and the similar fusion mechanism; the test results show that the polypeptides can achieve the commonality of the human coronavirus, ie., the similar HR region and the same fusion mechanism mediated by the coronavirus S protein so as to provide a series of HCoV-EK polypeptides, wherein the polypeptides provide good inhibition effects for currently popular human coronaviruses, and further provide good inhibition activity for SARS virus (RsSHC014-CoV or RsW1V1-CoV) possibly infecting human; and the polypeptides of the present invention can provide the prevention and treatment candidate drug for the currently popular human coronaviruses and the novel human coronavirus possibly emerging in the future.

Description

technical field [0001] The invention belongs to the field of biomedicine and relates to a polypeptide for inhibiting human coronavirus infection, in particular to a polypeptide capable of broadly inhibiting human coronavirus infection and an application thereof. [0002] technical background [0003] Data show that a new type of pathogen was first discovered in Guangzhou, China in 2002, which caused severe acute respiratory syndrome (Severe Acute Respiratory Syndrome, SARS), also known as infectious atypical pneumonia. Respiratory syndrome coronavirus (Severe acute respiratory syndrome coronavirus, SARS-CoV). As of July 2003, the disease has spread to 29 countries and regions around the world, with more than 8,000 confirmed cases and an average death rate of more than 10%. In 2012, another new type of coronavirus broke out in the Middle East, the Middle East respiratory coronavirus (Middle East respiratory Syndrome coronavirus, MERS-CoV), according to the World Health Organi...

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Problems solved by technology

[0005] At present, in the research and development of inhibitors for this type of virus, the S1 and S2 regions of the S protein are two important targets. Among them, the entry inhibitors for the S1 region are mainly antibodies, although these antibodies are specific to specific The virus has good neutralizing activity, but it has no cross-protection effect on other human coronaviruses; studies have shown that although SARS-CoV and its similar virus RsSHC014-CoV have high gene homology and the same receptors, However, SARS-CoV-specific antibodies still lack neutralizing activity against RsSHC014-CoV (references: Menachery, V.D., B.L.Yount, Jr., K.Debbink, S.Agnihothram, L.E.Gralinski, J.A.Plante, R.L.Graham, T. .Scobey, X.Y.Ge, E.F.Donaldson, S.H.Randell, A.Lanzavecchia, W.A.Marasco, Z.L.Shi, and R.S.Baric. 2015. A SARS-like cluster of circulating bat coronaviruses showspotential for human emergence. Nat Med 21:1508- 1513.); The entry inhibitors targeting the S2 region are mainly polypeptide drugs, and most of these entry inhibitors are derived from the amino acid sequence of the heptapeptide repeat region 2 (HR2) of the virus S2 protein; the HR2 polypeptide can bind to the heptapeptide of the virus The repeat region 1 (HR1) trimer binds to form a stable heterologous 6HB, which prevents the binding of the viral HR2 to the viral HR1 trimer, preventing them from forming homologous 6HB, thereby inhibiting the fusion of the viral membrane and the target cell membrane , which also inhibits the viral gene from entering the target cell membrane for replication (such as figure 1 shown); at present, polypeptide entry inhibitors with the same mechanism of action have played an important role in the treatment of HIV (HIV), for example, Enfuvirtide (Enfuvirtide, Fuzeon, also known as T20) is a US FDA The first polypeptide HIV entry inhibitor approved in the world, which is currently used in the clinical treatment of AIDS, has a good effect on those patients who have developed resistance to HIV reverse transcriptase inhibitors; one of the inventors of this application One - Jiang Shibo is the inventor of the T20 drug prototype polypeptide (peptide 637-666) (US Patent No.: 5,444,044)

[0006] The previous study of the present application found that in the S2 region of human coronavirus, the amino acid sequence of the heptapeptide repeat domain (HR) has a high degree of similarity, and its mechanism of fusion through the formation of six helices is very similar. Spectrum human coronavirus peptide inhibitors provide an important theoretical basis; however, the current design of peptide entry inhibitors is only based on the amino acid sequence or six-helix structure of the virus's own HR2, which still lacks broad-spectrum Therefore, the currently reported human coronavirus peptide inhibitors often lack broad-spectrum antiviral effects (references: Lu, L., Q.Liu, Y.Zhu, K.H.Chan, L.Qin, Y. Li, Q.Wang, J.F.Chan, L.Du, F.Yu, C.Ma, S.Ye, K.Y.Yuen, R.Zhang, and S.Jiang. 2014. Structure-based discovery of Middle East respiratory syndrome coronavirus fusion inhibitor .Nat Commun 5:3067. and Gao,J.,G.Lu,J.Qi,Y.Li,Y.Wu,Y.Deng,H.Geng,H.Li,Q.Wang,H.Xiao,W .Tan, J.Yan, and G.F.Gao.2013.Structure of the fusion core and inhibition of fusion by a heptadrepeat peptide derived from the S protein of Middle East respiratory syndrome coronavirus.J Virol87:13134-13140.)

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