A biochemical understanding of the mechanism of action of remdesivir against SARS-CoV-2 polymerase
Remdesivir (RDV) is an approved direct antiviral agent that targets the RNA-dependent RNA polymerase (RdRp) of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), the causative agent of COVID-19. Employing a biochemical approach, this presentation will demonstrate how RDV in its active triphosphate form (RDV-TP) inhibits SARS-CoV-2 viral RNA synthesis at the molecular level. This collection of work uncovered the following:
(i) RDV-TP is incorporated more efficiently than in its natural counterpart ATP.
(ii) Extension of RDV-monophosphate (MP) in the primer-strand results in a steric clash with Ser-861 of SARS-CoV-2 RdRp and consequently delayed-chain termination. Increasing NTP concentrations can overcome this inhibition and this read-through generates RNAs with embedded RDV-MP.
(iii) During second strand synthesis, a steric conflict between the embedded RDV-MP and the conserved motif F in RdRp provides another opportunity for inhibition.
Our data suggest that two adjacent RDV-MP residues in the template significantly enhance inhibition of the SARS-CoV-2 RdRp. The combined biochemical studies provide a detailed picture of the mechanism of action of RDV. Together, the data will help to guide the development of the next generation of antivirals targeting the SARS-CoV-2 RdRp and other viral polymerases.
Calvin Gordon is a 4th year PhD Candidate studying at the 海角社区, working in the lab of Dr. Matthias Götte. His research focuses on investigating broad-spectrum nucleotide analogues against the RNA-dependent RNA polymerase of different RNA viruses, including SARS-CoV-2. He has a BSc from Mount Royal University and worked as an Undergraduate Research Assistant there until he joined the 海角社区 in 2019. In 2022 he received several honors and awards including the Andrew Stewart Memorial Graduate Prize, the Canada Graduate Scholarship Doctoral Award and the President’s Doctoral Prize of Distinction.