Mechanism of Inhibition of the Reproduction of SARS-CoV-2 and Ebola Viruses by Remdesivir.

Biochemistry
Jimin WangVictor S Batista

Abstract

Remdesivir is an antiviral drug initially designed against the Ebola virus. The results obtained with it both in biochemical studies in vitro and in cell line assays in vivo were very promising, but it proved to be ineffective in clinical trials. Remdesivir exhibited far better efficacy when repurposed against SARS-CoV-2. The chemistry that accounts for this difference is the subject of this study. Here, we examine the hypothesis that remdesivir monophosphate (RMP)-containing RNA functions as a template at the polymerase site for the second run of RNA synthesis, and as mRNA at the decoding center for protein synthesis. Our hypothesis is supported by the observation that RMP can be incorporated into RNA by the RNA-dependent RNA polymerases (RdRps) of both viruses, although some of the incorporated RMPs are subsequently removed by exoribonucleases. Furthermore, our hypothesis is consistent with the fact that RdRp of SARS-CoV-2 selects RMP for incorporation over AMP by 3-fold in vitro, and that RMP-added RNA can be rapidly extended, even though primer extension is often paused when the added RMP is translocated at the i + 3 position (with i the nascent base pair at an initial insertion site of RMP) or when the concentrations of th...Continue Reading

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Citations

Jul 28, 2021·Journal of Chemical Information and Modeling·Hazem MslatiArtem Cherkasov
Sep 1, 2021·Current Opinion in Pharmacology·Chiranjib Chakraborty
Oct 23, 2021·Biochemical Pharmacology·Erik De Clercq

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