Bisubstrate Inhibitors of Severe Acute Respiratory Syndrome Coronavirus-2 Nsp14 Methyltransferase

Eunkyung Jung, Ruben Soto-Acosta, Jiashu Xie, Daniel Wilson, Christine D Dreis, Ryuichi Majima, Tiffany Edwards, Robert J. Geraghty, Liqiang Chen

Research output: Contribution to journalArticlepeer-review

1 Scopus citations

Abstract

Taking advantage of the uniquely constricted active site of SARS-CoV-2 Nsp14 methyltransferase, we have designed bisubstrate inhibitors interacting with the SAM and RNA substrate binding pockets. Our efforts have led to nanomolar inhibitors including compounds 3 and 10. As a prototypic inhibitor, compound 3 also has an excellent selectivity profile over a panel of human methyltransferases. Remarkably, C-nucleoside 10 exhibits high antiviral activity and low cytotoxicity, leading to a therapeutic index (CC50/EC50) greater than 139. Furthermore, a brief metabolic profiling of these two compounds suggests that they are less likely to suffer from major metabolic liabilities. Moreover, computational docking studies point to protein-ligand interactions that can be exploited to enhance inhibitory activity. In short, discovery of inhibitor 10 clearly demonstrates that potent and selective anti-SARS-CoV-2 activity can be achieved by targeting the Nsp14 methyltransferase. Therefore, the current work strongly supports the continued pursuit of Nsp14 methyltransferase inhibitors as COVID-19 therapeutics.

Original languageEnglish (US)
Pages (from-to)1477-1484
Number of pages8
JournalACS Medicinal Chemistry Letters
Volume13
Issue number9
DOIs
StatePublished - Sep 8 2022

Bibliographical note

Funding Information:
The reported work was supported by the Center of Drug Design at the University of Minnesota. The following reagent was deposited by the Centers for Disease Control and Prevention and obtained through BEI Resources, NIAID, NIH: SARS-Related Coronavirus 2, Isolate USA-WA1/2020, NR-52281.

Publisher Copyright:
© 2022 American Chemical Society. All rights reserved.

Keywords

  • antiviral
  • bisubstrate inhibitor
  • methyltransferase inhibitor
  • Nsp14
  • SARS-CoV-2

PubMed: MeSH publication types

  • Journal Article

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