The outbreak of severe acute respiratory syndrome coronavirus 2(SARSCoV-2)has developed into an unprecedented global pandemic.Nucleoside analogs,such as Remdesivir and Favipiravir,can serve as the firstline broad-spec...The outbreak of severe acute respiratory syndrome coronavirus 2(SARSCoV-2)has developed into an unprecedented global pandemic.Nucleoside analogs,such as Remdesivir and Favipiravir,can serve as the firstline broad-spectrum antiviral drugs by targeting the viral polymerases.However,the underlying mechanisms for the antiviral efficacies of these drugs are far from well understood.Here,we reveal that Favipiravir,as a pyrazine derivative,could be incorporated into the viral RNA products by mimicking both adenine and guanine nucleotides.This drug thus inhibits viral replication mainly by inducing mutations in progeny RNAs,different from Remdesivir or other RNA-terminating nucleoside analogs that impair the elongation of RNA products.We further determined the cryo-EM structure of Favipiravir bound to the replicating polymerase complex of SARSCoV-2 in the pre-catalytic state.This structure provides a missing snapshot for visualizing the catalysis dynamics of coronavirus polymerase,and reveals an unexpected base-pairing pattern between Favipiravir and pyrimidine residues that may explain its capacity for mimicking both adenine and guanine nucleotides.These findings shed light on the mechanism of coronavirus polymerase catalysis and provide a rational basis for developing antiviral drugs to combat the SARS-CoV-2 pandemic.展开更多
基金We thank all staff members in the Center of Biological Imaging(CBI),the Institute of Biophysics(IBP),and the Chinese Academy of Sciences(CAS)for assistance with data collection.This study was supported by the Strategic Priority Research Program of CAS(XDB29010000)the National Science and Technology Major Project(2018ZX10101004)+3 种基金the National Key Research and Development Program of China(2020YFC0845900)the National Natural Science Foundation of China(NSFC)(82041016,81871658,and 81802010)a grant from the Bill&Melinda Gates Foundation,and is partially supported by the Yanqi Lake Meeting organized by the Academic Divisions of CAS.M.W.is supported by the National Science and Technology Major Project(2018ZX09711003)the National Natural Science Foundation of China(NSFC)(81802007).R.P.is supported by the Young Elite Scientist Sponsorship Program(YESS)by the China Association for Science and Technology(CAST)(2018QNRC001).Y.S.is also supported by the Youth Innovation Promotion Association of CAS.
文摘The outbreak of severe acute respiratory syndrome coronavirus 2(SARSCoV-2)has developed into an unprecedented global pandemic.Nucleoside analogs,such as Remdesivir and Favipiravir,can serve as the firstline broad-spectrum antiviral drugs by targeting the viral polymerases.However,the underlying mechanisms for the antiviral efficacies of these drugs are far from well understood.Here,we reveal that Favipiravir,as a pyrazine derivative,could be incorporated into the viral RNA products by mimicking both adenine and guanine nucleotides.This drug thus inhibits viral replication mainly by inducing mutations in progeny RNAs,different from Remdesivir or other RNA-terminating nucleoside analogs that impair the elongation of RNA products.We further determined the cryo-EM structure of Favipiravir bound to the replicating polymerase complex of SARSCoV-2 in the pre-catalytic state.This structure provides a missing snapshot for visualizing the catalysis dynamics of coronavirus polymerase,and reveals an unexpected base-pairing pattern between Favipiravir and pyrimidine residues that may explain its capacity for mimicking both adenine and guanine nucleotides.These findings shed light on the mechanism of coronavirus polymerase catalysis and provide a rational basis for developing antiviral drugs to combat the SARS-CoV-2 pandemic.
