The effects of Remdesivir's functional groups on its antiviral potency and resistance against the SARS-CoV-2 polymerase.

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  • Additional Information
    • Source:
      Publisher: Elsevier Country of Publication: Netherlands NLM ID: 8109699 Publication Model: Print-Electronic Cited Medium: Internet ISSN: 1872-9096 (Electronic) Linking ISSN: 01663542 NLM ISO Abbreviation: Antiviral Res Subsets: MEDLINE
    • Publication Information:
      Publication: Amsterdam : Elsevier
      Original Publication: [Amsterdam ; New York : Elsevier/North-Holland Biomedical Press, c1981-
    • Subject Terms:
      Alanine*/analogs & derivatives ; Alanine*/pharmacology ; Adenosine Monophosphate*/analogs & derivatives ; Adenosine Monophosphate*/pharmacology ; Antiviral Agents*/pharmacology ; SARS-CoV-2*/drug effects ; Virus Replication*/drug effects ; COVID-19 Drug Treatment* ; Drug Resistance, Viral*; Humans ; RNA, Viral/genetics ; RNA, Viral/biosynthesis ; Coronavirus RNA-Dependent RNA Polymerase/antagonists & inhibitors ; Chlorocebus aethiops ; Animals ; Vero Cells
    • Abstract:
      Remdesivir (RDV, Veklury®) is the first FDA-approved antiviral treatment for COVID-19. It is a nucleotide analogue (NA) carrying a 1'-cyano (1'-CN) group on the ribose and a pseudo-adenine nucleobase whose contributions to the mode of action (MoA) are not clear. Here, we dissect these independent contributions by employing RDV-TP analogues. We show that while the 1'-CN group is directly responsible for transient stalling of the SARS-CoV-2 replication/transcription complex (RTC), the nucleobase plays a role in the strength of this stalling. Conversely, RNA extension assays show that the 1'-CN group plays a role in fidelity and that RDV-TP can be incorporated as a GTP analogue, albeit with lower efficiency. However, a mutagenic effect by the viral polymerase is not ascertained by deep sequencing of viral RNA from cells treated with RDV. We observe that once added to the 3' end of RNA, RDV-MP is sensitive to excision and its 1'-CN group does not impact its nsp14-mediated removal. A >14-fold RDV-resistant SARS-CoV-2 isolate can be selected carrying two mutations in the nsp12 sequence, S759A and A777S. They confer both RDV-TP discrimination over ATP by nsp12 and stalling during RNA synthesis, leaving more time for excision-repair and potentially dampening RDV efficiency. We conclude that RDV presents a multi-faced MoA. It slows down or stalls overall RNA synthesis but is efficiently repaired from the primer strand, whereas once in the template, read-through inhibition adds to this effect. Its efficient incorporation may corrupt proviral RNA, likely disturbing downstream functions in the virus life cycle.
      Competing Interests: Declaration of competing interest The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.
      (Copyright © 2024 The Authors. Published by Elsevier B.V. All rights reserved.)
    • Contributed Indexing:
      Keywords: Excision; MoA; Nucleotide analogue; Polymerization; Remdesivir; Resistance; SARS-CoV-2
    • Accession Number:
      3QKI37EEHE (remdesivir)
      OF5P57N2ZX (Alanine)
      415SHH325A (Adenosine Monophosphate)
      0 (Antiviral Agents)
      0 (RNA, Viral)
      EC 2.7.7.48 (Coronavirus RNA-Dependent RNA Polymerase)
    • Publication Date:
      Date Created: 20241107 Date Completed: 20241210 Latest Revision: 20241210
    • Publication Date:
      20241211
    • Accession Number:
      10.1016/j.antiviral.2024.106034
    • Accession Number:
      39510431