SARS-CoV-2 and its emerging variants continue to pose a significant global public health threat.The SARS-CoV-2 main protease(M^(pro))is a critical target for the development of antiviral agents that can inhibit viral ...SARS-CoV-2 and its emerging variants continue to pose a significant global public health threat.The SARS-CoV-2 main protease(M^(pro))is a critical target for the development of antiviral agents that can inhibit viral replication and transcription.In this study,we identified chebulagic acid(CHLA),isolated from Terminalia chebula Retz.,as a potent non-peptidomimetic and non-covalent M^(pro) inhibitor.CHLA exhibited intermolecular interactions and provided significant protection to Vero E6 cells against a range of SARS-CoV-2 variants,including the wild-type,Delta,Omicron BA.1.1,BA.2.3,BA.4,and BA.5,with EC_(50) values below 2μmol/L.Moreover,in vivo studies confirmed the antiviral efficacy of CHLA in K18-hACE2 mice.Notably,CHLA bound to a unique groove at the interface between M^(pro) domains I and II,which was revealed by the high-resolution crystal structure(1.4 A˚)of the M^(pro)—CHLA complex,shrinking the substrate binding pocket of M^(pro) and inducing M^(pro) aggregation.CHLA was pro-posed to act as an allosteric inhibitor.Pharmacokinetic profiling and safety assessments underscore CHLA’s potential as a promising broad-spectrum antiviral candidate.These findings report a novel bind-ing site on M^(pro) and identify antiviral activity of CHLA,providing a robust framework for lead com-pounds discovery and elucidating the underlying molecular mechanisms of inhibition.展开更多
基金funded by the National Natural Science Founda-tion of China(82104372 to Min Zhang,32200131 to Yao Zhao)Science and Technology Project of Haihe Laboratory of Modern Chinese Medicine(22HHZYJC00007 to Min Zhang)Shenzhen High-level Hospital Construction Fund(23264G1001 to Yao Zhao).
文摘SARS-CoV-2 and its emerging variants continue to pose a significant global public health threat.The SARS-CoV-2 main protease(M^(pro))is a critical target for the development of antiviral agents that can inhibit viral replication and transcription.In this study,we identified chebulagic acid(CHLA),isolated from Terminalia chebula Retz.,as a potent non-peptidomimetic and non-covalent M^(pro) inhibitor.CHLA exhibited intermolecular interactions and provided significant protection to Vero E6 cells against a range of SARS-CoV-2 variants,including the wild-type,Delta,Omicron BA.1.1,BA.2.3,BA.4,and BA.5,with EC_(50) values below 2μmol/L.Moreover,in vivo studies confirmed the antiviral efficacy of CHLA in K18-hACE2 mice.Notably,CHLA bound to a unique groove at the interface between M^(pro) domains I and II,which was revealed by the high-resolution crystal structure(1.4 A˚)of the M^(pro)—CHLA complex,shrinking the substrate binding pocket of M^(pro) and inducing M^(pro) aggregation.CHLA was pro-posed to act as an allosteric inhibitor.Pharmacokinetic profiling and safety assessments underscore CHLA’s potential as a promising broad-spectrum antiviral candidate.These findings report a novel bind-ing site on M^(pro) and identify antiviral activity of CHLA,providing a robust framework for lead com-pounds discovery and elucidating the underlying molecular mechanisms of inhibition.
