Unveiling the “Template-Dependent” Inhibition on the Viral Transcription of SARS-CoV-2

Xueying Luo, Xiaowei Wang, Yuan Yao, Xin Gao, Lu Zhang

Research output: Contribution to journalArticlepeer-review

5 Scopus citations

Abstract

Remdesivir is one nucleotide analogue prodrug capable to terminate RNA synthesis in SARS-CoV-2 RNA-dependent RNA polymerase (RdRp) by two distinct mechanisms. Although the “delayed chain termination” mechanism has been extensively investigated, the “template-dependent” inhibitory mechanism remains elusive. In this study, we have demonstrated that remdesivir embedded in the template strand seldom directly disrupted the complementary NTP incorporation at the active site. Instead, the translocation of remdesivir from the +2 to the +1 site was hindered due to the steric clash with V557. Moreover, we have elucidated the molecular mechanism characterizing the drug resistance upon V557L mutation. Overall, our studies have provided valuable insight into the “template-dependent” inhibitory mechanism exerted by remdesivir on SARS-CoV-2 RdRp and paved venues for an alternative antiviral strategy for the COVID-19 pandemic. As the “template-dependent” inhibition occurs across diverse viral RdRps, our findings may also shed light on a common acting mechanism of inhibitors.
Original languageEnglish (US)
Pages (from-to)7197-7205
Number of pages9
JournalThe Journal of Physical Chemistry Letters
DOIs
StatePublished - Jul 30 2022

Bibliographical note

KAUST Repository Item: Exported on 2022-09-14
Acknowledged KAUST grant number(s): FCC/1/1976-44-01, FCC/1/1976-45-01
Acknowledgements: The authors acknowledge the financial support from the National Key R&D program of China (2021YFA1502300), the National Natural Science Foundation of China (21733007), the Hong Kong Research Grant Council NSFC/RGC Joint Research Scheme (N_HKUST635/20) and the King Abdullah University of Science and Technology (KAUST) Office of Research Administration (ORA) under Award No FCC/1/1976-44-01 and FCC/1/1976-45-01. This research made use of the resources of the Supercomputing Laboratory at King Abdullah University of Science & Technology (KAUST) as well as the computing resources of the X-GPU cluster supported by the Hong Kong Research Grant Council Collaborative Research Fund: C6021-19EF.

ASJC Scopus subject areas

  • General Materials Science

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