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PreprintCited by 52SARS-CoV-2 and COVID-19 ResearchComputational Drug Discovery MethodsProtein Structure and Dynamics

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Role of 1’-Ribose Cyano Substitution for Remdesivir to Effectively Inhibit Nucleotide Addition and Proofreading in SARS-CoV-2 Viral RNA Replication

Open access
Zhang, Lu, Zhang, Dong, Wang, Xiaowei, Yuan, Congmin, Li, Yongfang, Jia, Xilin, Gao, Xin, Yen, Hui-Ling, Cheung, Peter Pak-Hang, Huang, Xuhui·2020·Physical Chemistry Chemical Physics
DOI 10.1101/2020.04.27.063859

Preprint — published as 10.1039/d0cp05948j · Paper page

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Abstract

COVID-19 has recently caused a global health crisis and an effective interventional therapy is urgently needed. SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) is a promising but challenging drug target due to its intrinsic proofreading exoribonuclease (ExoN). Remdesivir targeting SARS-CoV-2 RdRp exerts high drug efficacy in vitro and in vivo . However, its underlying inhibitory mechanisms remain elusive. Here, we performed all-atom molecular dynamics simulations with an accumulated simulation time of 24 microseconds to elucidate the molecular mechanisms underlying the inhibitory effects of Remdesivir. We found that Remdesivir’s 1’-cyano group of possesses the dual role of inhibiting nucleotide addition and proofreading. The presence of its polar 1’-cyano group at an upstream site in RdRp causes instability and hampers RdRp translocation. This leads to a delayed chain termination of RNA extension, which may also subsequently reduce the likelihood for Remdesivir to be cleaved by ExoN acting on the 3’-terminal nucleotide. In addition, our simulations suggest that Remdesivir’s 1’-cyano group can also disrupt the cleavage active site of ExoN via steric interactions, leading to a further reduced cleavage efficiency. Our work provides plausible molecular mechanisms on how Remdesivir inhibits viral RNA replication and may guide rational design for new treatments of COVID-19 targeting viral replication.

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Metadata

Authors
Zhang, L., Zhang, D., Wang, X., Yuan, C., Li, Y., Jia, X., Gao, X., Yen, H.-L., Cheung, P. P.-H., & Huang, X.
Affiliations
  • Chinese Academy of Sciences (CN)
  • Hong Kong University of Science and Technology (HK)
  • King Abdullah University of Science and Technology (SA)
  • University of Hong Kong (HK)
Corresponding author
  • Zhang, Lu
  • Cheung, Peter Pak-Hang
  • Huang, Xuhui
ORCID
Venue
Physical Chemistry Chemical Physics
Publisher
openRxiv
Published
2020-04-27
Volume
23
Issue
10
Pages
5852-5863
ISSN
1463-9076 (ISSN-L)
DOI
10.1101/2020.04.27.063859
OpenAlex
W3130661276
Cited by
52
References
1
Citations by year
2026: 1 · 2025: 6 · 2024: 5 · 2023: 7 · 2022: 16 · 2021: 15 · 2020: 2
FWCI
3.40
Type
journal article
Language
en
Open access
Licence
www.biorxiv.org/about/FAQ#license (vor)
Locations
  • Physical Chemistry Chemical Physics (publishedVersion)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion)
  • PubMed (publishedVersion)
  • Rare & Special e-Zone (The Hong Kong University of Science and Technology) (submittedVersion)
  • King Abdullah University of Science and Technology Repository (King Abdullah University of Science and Technology) (submittedVersion)
Funders
  • National Natural Science Foundation of China (ITCPD/17-9, 21733007, 21803071)
  • Research Grants Council, University Grants Committee (16307718, 16318816, 16301319, T13-605/18W, AoE/P705/16)
  • Innovation and Technology Commission (ITC PD/17-9)
  • King Abdullah University of Science and Technology (URF/1/4098–01-01, REI/1/0018–01-01, REI/1/4473- 01-01, FCC/1/1976-23, FCC/1/1976-18, FCC/1/1976-26)
  • Science, Technology and Innovation Commission of Shenzhen Municipality (JCYJ20170413173837121)
  • Shenzhen Municipal Science and Technology Innovation Council (ITCPD/17-9, JCYJ20170413173837121)
Topics
  • Health Sciences › Medicine › Infectious Diseases › SARS-CoV-2 and COVID-19 Research
  • Life Sciences › Pharmacology, Toxicology and Pharmaceutics › Drug Discovery › Computational Drug Discovery Methods
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Structure and Dynamics
Keywords
remdesivir, SARS-CoV-2, RNA-dependent RNA polymerase, exonuclease proofreading, salt bridges, electrostatic interactions, steric interactions, viral RNA replication inhibition, COVID-19 antiviral therapy, molecular dynamics simulation
MeSH terms
COVID-19, SARS-CoV-2, COVID-19 Drug Treatment, Adenosine Monophosphate, Alanine, Cyanides, Humans, Nucleotides, Ribose, RNA-Dependent RNA Polymerase, Virus Replication, Catalytic Domain, Static Electricity, Molecular Dynamics Simulation

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