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dc.contributor.authorZhang, Lu
dc.contributor.authorZhang, Dong
dc.contributor.authorWang, Xiaowei
dc.contributor.authorYuan, Congmin
dc.contributor.authorLi, Yongfang
dc.contributor.authorJia, Xilin
dc.contributor.authorGao, Xin
dc.contributor.authorYen, Hui-Ling
dc.contributor.authorCheung, Peter Pak-Hang
dc.contributor.authorHuang, Xuhui
dc.identifier.citationZhang, L., Zhang, D., Wang, X., Yuan, C., Li, Y., Jia, X., … Huang, X. (2021). 1′-Ribose cyano substitution allows Remdesivir to effectively inhibit nucleotide addition and proofreading during SARS-CoV-2 viral RNA replication. Physical Chemistry Chemical Physics. doi:10.1039/d0cp05948j
dc.description.abstractCOVID-19 has recently caused a global health crisis and an effective interventional therapy is urgently needed. Remdesivir is one effective inhibitor for SARS-CoV-2 viral RNA replication. It supersedes other NTP analogues because it not only terminates the polymerization activity of RNA-dependent RNA polymerase (RdRp), but also inhibits the proofreading activity of intrinsic exoribonuclease (ExoN). Even though the static structure of Remdesivir binding to RdRp has been solved and biochemical experiments have suggested it to be a "delayed chain terminator", the underlying molecular mechanisms is not fully understood. Here, we performed all-atom molecular dynamics (MD) simulations with an accumulated simulation time of 24 microseconds to elucidate the inhibitory mechanism of Remdesivir on nucleotide addition and proofreading. We found that when Remdesivir locates at an upstream site in RdRp, the 1'-cyano group experiences electrostatic interactions with a salt bridge (Asp865-Lys593), which subsequently halts translocation. Our findings can supplement the current understanding of the delayed chain termination exerted by Remdesivir and provide an alternative molecular explanation about Remdesivir's inhibitory mechanism. Such inhibition also reduces the likelihood of Remdesivir to be cleaved by ExoN acting on 3'-terminal nucleotides. Furthermore, our study also suggests that Remdesivir's 1'-cyano group can disrupt the cleavage site of ExoN via steric interactions, leading to a further reduction in the cleavage efficiency. Our work provides plausible and novel mechanisms at the molecular level of how Remdesivir inhibits viral RNA replication, and our findings may guide rational design for new treatments of COVID-19 targeting viral replication.
dc.description.sponsorshipThe authors acknowledge the National Natural Science Foundation of China Grants [grant number 21733007 and 21803071 to L. Z.], the Shenzhen Science and Technology Innovation Committee [grant number JCYJ20170413173837121 to X. H.], the Hong Kong Research Grant Council [grant number 16307718, 16318816, AoE/P-705/16, and T13-605/18-W to X. H.; 16301319 to P. P. C.], the Innovation and Technology Commission [grant number ITCPD/17-9 to X. H.] and the King Abdullah University of Science and Technology (KAUST) Office of Sponsored Research (OSR) [Award No. FCC/1/1976-18, FCC/1/1976-23, FCC/1/1976-26, URF/1/4098-01-01, REI/1/4473-01-01, and REI/1/0018-01-01 to X. G.]. This research made use of the computing resources of the Supercomputing Laboratory at King Abdullah University of Science and Technology.
dc.publisherRoyal Society of Chemistry (RSC)
dc.rightsArchived with thanks to Physical chemistry chemical physics : PCCP
dc.title1'-Ribose cyano substitution allows Remdesivir to effectively inhibit nucleotide addition and proofreading during SARS-CoV-2 viral RNA replication.
dc.contributor.departmentComputer Science Program
dc.contributor.departmentComputational Bioscience Research Center (CBRC)
dc.contributor.departmentComputer, Electrical and Mathematical Sciences and Engineering (CEMSE) Division
dc.identifier.journalPhysical Chemistry Chemical Physics
dc.contributor.institutionState Key Laboratory of Structural Chemistry
dc.contributor.institutionFujian Institute of Research on the Structure of Matter
dc.contributor.institutionChinese Academy of Sciences
dc.contributor.institutionThe Hong Kong University of Science and Technology-Shenzhen Research Institute
dc.contributor.institutionDepartment of Chemistry
dc.contributor.institutionCentre of Systems Biology and Human Health
dc.contributor.institutionComputational Bioscience Research Center, Computer, Electrical and Mathematical Sciences Engineering Division
dc.contributor.institutionSaudi Arabia
dc.contributor.institutionSchool of Public Health
dc.contributor.institutionLKS Faculty of Medicine
dc.contributor.institutionThe University of Hong Kong
dc.contributor.institutionHong Kong
kaust.personGao, Xin
kaust.acknowledged.supportUnitOffice of Sponsored Research (OSR)
kaust.acknowledged.supportUnitSupercomputing Laboratory

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