The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million s...The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million small molecules against the main protease(M^(pro))and papain like protease(PL^(pro)),two major proteases in severe acute respiratory syndrome-coronavirus 2 genome,and identified 1851M^(pro)inhibitors and 205 PL^(pro)inhibitors with low nmol/l activity of the best hits.Among these inhibitors,eight small molecules showed dual inhibition effects on both M^(pro)and PL^(pro),exhibiting potential as better candidates for COVID-19 treatment.The best inhibitors of each protease were tested in antiviral assay,with over 40%of M^(pro)inhibitors and over 20%of PL^(pro)inhibitors showing high potency in viral inhibition with low cytotoxicity.The X-ray crystal structure of SARS-CoV-2 M^(pro)in complex with its potent inhibitor 4a was determined at 1.8Åresolution.Together with docking assays,our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.展开更多
Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell li...Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell lines derived from diverse species,including bats,mice,hamsters,rats,chickens,pigs,nonhuman primates,and humans,implying its high risk of cross‐species infection.However,its receptor is still unknown.In this study,the receptor‐binding domain of the SADS‐CoV spike(S)protein was purified and then subjected to affinity purification(AP)‐coupled mass spectrometry(MS)‐based proteomic analysis to identify the interactors of the SADS‐CoV S protein.Forty‐three host proteins were identified,and a Gene Ontology analysis indicated that these interactors can be grouped into categories such as“cell‐cell adhesion”,“translation”“viral transcription”,suggesting that these processes may participate in the SADS‐CoV life cycles.RNA interference‐based screening of these interactors indicated that PPIB and vimentin can affect SADS‐CoV replication.Our study provides an overarching view into the host interactome of the SADS‐CoV S protein and highlights potential targets for the development of therapeutics against SADS‐CoV.展开更多
Dear Editor,Since the beginning of 2020,the Coronavirus(CoV)Disease 2019(COVID-19)pandemic has posed formidable challenges to public health security.The main protease(Mpro,3CLpro)of CoVs plays essential roles in viral...Dear Editor,Since the beginning of 2020,the Coronavirus(CoV)Disease 2019(COVID-19)pandemic has posed formidable challenges to public health security.The main protease(Mpro,3CLpro)of CoVs plays essential roles in viral replication,making them attractive targets for antiviral drug development.展开更多
基金supported by the National Key R&D Program of China 2018YFA0507000(B.W,Q.Z.),2018ZX09735001(Y.J.)and 2020YFC0844500(J.L.),the National Science Foundation of China grants 31825010(B.W.),81525024(Q.Z.),81673489(J.L),the Key Research Program of Frontier Sciences,CAS grants QYZDB-SSWSMC024(B.W.)and QYZDB-SSW-SMC054(Q.Z.),Fund of Chinese Academy of Sciences 2020YJFK0105(J.L.),Chinese Academy of Engineering and Jack Ma Foundation 2020-CMKYGG-05(J.D.),the Shanghai Science and Technology Development Funds 20431900200(J.L.)and K.C.Wong Education Foundation(J.L.),Fund of Youth Innovation Promotion Association 2018319(X.C.),and the Hubei Science and Technology Project 2020FCA003(G.X.).Fund of Chinese Academy of Sciences 2020YJFK0105(J.L.)。
文摘The global COVID-19 coronavirus pandemic has infected over 109 million people,leading to over 2 million deaths up to date and still lacking of effective drugs for patient treatment.Here,we screened about 1.8 million small molecules against the main protease(M^(pro))and papain like protease(PL^(pro)),two major proteases in severe acute respiratory syndrome-coronavirus 2 genome,and identified 1851M^(pro)inhibitors and 205 PL^(pro)inhibitors with low nmol/l activity of the best hits.Among these inhibitors,eight small molecules showed dual inhibition effects on both M^(pro)and PL^(pro),exhibiting potential as better candidates for COVID-19 treatment.The best inhibitors of each protease were tested in antiviral assay,with over 40%of M^(pro)inhibitors and over 20%of PL^(pro)inhibitors showing high potency in viral inhibition with low cytotoxicity.The X-ray crystal structure of SARS-CoV-2 M^(pro)in complex with its potent inhibitor 4a was determined at 1.8Åresolution.Together with docking assays,our results provide a comprehensive resource for future research on anti-SARS-CoV-2 drug development.
基金supported by National Natural Science Foundation of China(31830096)the Open Research Fund Program of Wuhan National Bio‐Safety Level 4 Lab of CAS(2020ACCP‐MS01)the Youth Innovation Promotion Association CAS(grants 2018367 to L.‐K.Z).
文摘Swine acute diarrhea syndrome coronavirus(SADS‐CoV)is a recently discovered coronavirus that causes severe and acute diarrhea and rapid weight loss in piglets.SADS‐CoV was reported to be capable of infecting cell lines derived from diverse species,including bats,mice,hamsters,rats,chickens,pigs,nonhuman primates,and humans,implying its high risk of cross‐species infection.However,its receptor is still unknown.In this study,the receptor‐binding domain of the SADS‐CoV spike(S)protein was purified and then subjected to affinity purification(AP)‐coupled mass spectrometry(MS)‐based proteomic analysis to identify the interactors of the SADS‐CoV S protein.Forty‐three host proteins were identified,and a Gene Ontology analysis indicated that these interactors can be grouped into categories such as“cell‐cell adhesion”,“translation”“viral transcription”,suggesting that these processes may participate in the SADS‐CoV life cycles.RNA interference‐based screening of these interactors indicated that PPIB and vimentin can affect SADS‐CoV replication.Our study provides an overarching view into the host interactome of the SADS‐CoV S protein and highlights potential targets for the development of therapeutics against SADS‐CoV.
基金M.L.was funded by the NSFC(82073292,81622002,81861130368)the SJTU Trans-med Awards Research,the Gaofeng Clinical Medicine Grant(828318)+6 种基金the Shanghai Excellent Youth Academic Leader Program(20XD1422700)the Shanghai Medical and Health Excellent Discipline Leader Development Plan(2018BR36)Shanghai Collaborative Innovation Center for Translational Medicine(TM201902)the Foundation of the National Facility for Translational Medicine(Shanghai)(TMSK-2020-003)the Newton Advanced Fellowship,and the Samuel Waxman Cancer Research Foundation.H.Y.was funded by the Science and Technology Commission of Shanghai Municipality(20431900200)the Department of Science and Technology of Guangxi Zhuang Autonomous Region(2020AB40007)L.Z.was funded by the NSFC(31970165).
文摘Dear Editor,Since the beginning of 2020,the Coronavirus(CoV)Disease 2019(COVID-19)pandemic has posed formidable challenges to public health security.The main protease(Mpro,3CLpro)of CoVs plays essential roles in viral replication,making them attractive targets for antiviral drug development.