4.8 Article

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

Journal

JOURNAL OF PHYSICAL CHEMISTRY LETTERS
Volume 13, Issue 31, Pages 7197-7205

Publisher

AMER CHEMICAL SOC
DOI: 10.1021/acs.jpclett.2c01314

Keywords

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Funding

  1. National Key R&D program of China [2021YFA1502300]
  2. National Natural Science Foundation of China [21733007]
  3. Hong Kong Research Grant Council NSFC/RGC Joint Research Scheme [N_HKUST635/20]
  4. King Abdullah University of Science and Technology (KAUST) Office of Research Administration (ORA) [FCC/1/1976-44-01, FCC/1/1976-45-01]
  5. Hong Kong Research Grant Council Collaborative Research Fund [C6021-19EF]

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This study has elucidated the template-dependent inhibitory mechanism of remdesivir on SARS-CoV-2 RdRp and identified the molecular mechanism of drug resistance caused by the V557L mutation.
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.

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