The antiviral compound remdesivir potently inhibits RNA-dependent RNA polymerase from Middle East respiratory syndrome coronavirus

By Calvin J. Gordon, E. Tchesnokov, Joy Y. Feng, D. Porter, M. Götte. Journal of Biological Chemistry, 2020

737 citations recorded by the source corpus.

Antiviral drugs for managing infections with human coronaviruses are not yet approved, posing a serious challenge to current global efforts aimed at containing the outbreak of severe acute respiratory syndrome–coronavirus 2 (CoV-2). Remdesivir (RDV) is an investigational compound with a broad spectrum of antiviral activities against RNA viruses, including severe acute respiratory syndrome–CoV and Middle East respiratory syndrome (MERS–CoV). RDV is a nucleotide analog inhibitor of RNA-dependent RNA polymerases (RdRps). Here, we co-expressed the MERS–CoV nonstructural proteins nsp5, nsp7, nsp8, and nsp12 (RdRp) in insect cells as a part a polyprotein to study the mechanism of inhibition of MERS–CoV RdRp by RDV. We initially demonstrated that nsp8 and nsp12 form an active complex. The triphosphate form of the inhibitor (RDV-TP) competes with its natural counterpart ATP. Of note, the selectivity value for RDV-TP obtained here with a steady-state approach suggests that it is more efficiently incorporated than ATP and two other nucleotide analogs. Once incorporated at position i, the inhibitor caused RNA synthesis arrest at position i + 3. Hence, the likely mechanism of action is delayed RNA chain termination. The additional three nucleotides may protect the inhibitor from excision by the viral 3′–5′ exonuclease activity. Together, these results help to explain the high potency of RDV against RNA viruses in cell-based assays.

Subfields: Infectious Diseases

View Paper: https://www.semanticscholar.org/paper/62843cf428a94a24f070acab1ad41a52ee2b2187

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In Infectious Diseases

1. Calvin J. Gordon
2. D. Porter
3. M. Götte
4. Joy Y. Feng
5. E. Tchesnokov

Citations in the corpus

• The FDA-approved drug ivermectin inhibits the replication of SARS-CoV-2 in vitro (2020, background): “This Brief Report raises the possibility that ivermectin could be a useful antiviral to limit SARS-CoV-2, in similar fashion to those already reported (Dong et al., 2020; Elfiky, 2020; Gordon et al., 2020; Li and De Clercq, 2020; Wang et al., 2020) ; until one of these is proven to be beneficial in ”
• Remdesivir: A Review of Its Discovery and Development Leading to Emergency Use Authorization for Treatment of COVID-19 (2020, background): “76 Interestingly, in vitro assays demonstrate that the triphosphate form of the inhibitor was incorporated at increased rates compared to natural nucleotide pools, 77 likely adding to strong antiviral potency of remdesivir through premature RNA synthesis termination.”
• Coronavirus Diseases (COVID-19) Current Status and Future Perspectives: A Narrative Review (2020, methodology): “use of remdesivir through an investigational new drug application has been described in various studies [44,45].”
• Remdesivir is a direct-acting antiviral that inhibits RNA-dependent RNA polymerase from severe acute respiratory syndrome coronavirus 2 with high potency (2020, positive): “We have recently expressed and purified an active complex composed of MERS nonstructural proteins nsp8 and nsp12 (17).”
• Structure of replicating SARS-CoV-2 polymerase (2020, background): “Remde-sivir shows antiviral activity against coronaviruses in cell culture and animals 8 , inhibits coronavirus RdRp 9,10 , and is currently tested in the clinic as a drug candidate for treating COVID-19 patients 11-13 .”