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 University of Alberta, 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 U of A 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.