Discovery of Novel Isofunctional SARS-CoV-2 NSP14 RNA Cap Methyltransferase Inhibitors by Structure-Based Virtual Screening

In early 2020, SARS-CoV-2 spread into a worldwide pandemic, causing more than 7 million deaths. Direct-acting antivirals (DAAs) complementing vaccines and mitigating severe disease in at-risk populations remain important. Here, we used a structure-based virtual screening (SBVS) workflow to identify new SAH-dependent inhibitors of the SARS-CoV-2 RNA cap methyltransferase NSP14. We virtually screened the Enamine and Sigma in-stock screening collections as well as the 3 orders of magnitude larger Enamine REAL make-on-demand compound library, which produced better docking scores and higher virtual hit rates. While biochemical testing of 145 in-stock library compounds yielded a single NSP14-specific inhibitor, 123 chemically synthesized Enamine REAL SBVS compounds contained 10 hits specifically inhibiting NSP14 with half-maximal inhibitory concentrations (IC<sub>50</sub>) below 10 μM. The new compounds were chemically distinct in atomic composition from any NSP14 inhibitors previously identified by conventional biochemical high-throughput screening (HTS) and may serve as starting points to develop novel SARS-CoV-2 DAAs.

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Publication Details

Journal
ACS Medicinal Chemistry Letters
Published
2025-08-15
DOI
https://doi.org/10.1021/acsmedchemlett.5c00339
Primary Topic
RNA and protein synthesis mechanisms
Type
article
Field-Weighted Citation Impact
0.00

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article

Discovery of Novel Isofunctional SARS-CoV-2 NSP14 RNA Cap Methyltransferase Inhibitors by Structure-Based Virtual Screening

David J. Huggins, Cindy Meyer, Hans-Heinrich Hoffmann, Charles M. Rice et al.
1 links
ACS Medicinal Chemistry Letters
RNA and protein synthesis mechanisms
article

Discovery of Novel Isofunctional SARS-CoV-2 NSP14 RNA Cap Methyltransferase Inhibitors by Structure-Based Virtual Screening

David J. Huggins, Cindy Meyer, Hans-Heinrich Hoffmann, Charles M. Rice, Aitor Garzia, Joshua Saul Davis, Oleg M. Ganichkin, Peter T. Meinke, Thomas Tuschl, Nigel J. Liverton, Stefan Steinbacher, Joseph Fraser Glickman, Mayako Michino, Michael W. Miller, Julius Nitsche
article en

Abstract

In early 2020, SARS-CoV-2 spread into a worldwide pandemic, causing more than 7 million deaths. Direct-acting antivirals (DAAs) complementing vaccines and mitigating severe disease in at-risk populations remain important. Here, we used a structure-based virtual screening (SBVS) workflow to identify new SAH-dependent inhibitors of the SARS-CoV-2 RNA cap methyltransferase NSP14. We virtually screened the Enamine and Sigma in-stock screening collections as well as the 3 orders of magnitude larger Enamine REAL make-on-demand compound library, which produced better docking scores and higher virtual hit rates. While biochemical testing of 145 in-stock library compounds yielded a single NSP14-specific inhibitor, 123 chemically synthesized Enamine REAL SBVS compounds contained 10 hits specifically inhibiting NSP14 with half-maximal inhibitory concentrations (IC<sub>50</sub>) below 10 μM. The new compounds were chemically distinct in atomic composition from any NSP14 inhibitors previously identified by conventional biochemical high-throughput screening (HTS) and may serve as starting points to develop novel SARS-CoV-2 DAAs.

ACS Medicinal Chemistry LettersVol. 16(9)
Cornell University (US), ProterixBio (United States) (US), Tri-Institutional Therapeutics Discovery Institute (US), Rockefeller University (US)
Division of Intramural Research, National Institute of Allergy and Infectious Diseases, Rockefeller University, Stavros Niarchos Foundation
Openalex Percentile: Top 81%
RNA and protein synthesis mechanisms
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