tetano
Editor, Senior Moderator
ACS Chem Biol
. 2025 Feb 5.
doi: 10.1021/acschembio.4c00458. Online ahead of print. Analogs of NIH Molecular Probe ML283 Are Potent SARS-CoV-2 Helicase Inhibitors
David N Frick[SUP] 1 [/SUP], Robert V Bavisotto[SUP] 1 [/SUP], Nicholas C Hopper[SUP] 1 [/SUP], Wilfred T Tysoe[SUP] 1 [/SUP]
Affiliations
The National Institutes of Health molecular probe ML283 was synthesized as a potent, selective inhibitor of the helicase encoded by the hepatitis C virus. Because modeling with AutoDock Vina predicted that ML283 might bind the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nonstructural protein 13 (nsp13) helicase, the effects of a collection of ML283 analogs and other hepatitis C virus (HCV) helicase inhibitors on the SARS-CoV-2 helicase were analyzed. Only modest impacts on nsp13-catalyzed ATP hydrolyses were observed with some compounds, most of which were analogs of the drug ebselen, not ML283. In contrast, a new molecular-beacon-based helicase assay revealed that ML283 and many ML283 analogs are potent SARS-CoV-2 helicase inhibitors. Analog potencies correlate with the binding energies predicted by modeling, which suggests that a pocket surrounded by the carboxy-terminal nsp13 RecA-like helicase motor domain might be exploitable for antiviral drug development.
. 2025 Feb 5.
doi: 10.1021/acschembio.4c00458. Online ahead of print. Analogs of NIH Molecular Probe ML283 Are Potent SARS-CoV-2 Helicase Inhibitors
David N Frick[SUP] 1 [/SUP], Robert V Bavisotto[SUP] 1 [/SUP], Nicholas C Hopper[SUP] 1 [/SUP], Wilfred T Tysoe[SUP] 1 [/SUP]
Affiliations
- PMID: 39910979
- DOI: 10.1021/acschembio.4c00458
The National Institutes of Health molecular probe ML283 was synthesized as a potent, selective inhibitor of the helicase encoded by the hepatitis C virus. Because modeling with AutoDock Vina predicted that ML283 might bind the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) nonstructural protein 13 (nsp13) helicase, the effects of a collection of ML283 analogs and other hepatitis C virus (HCV) helicase inhibitors on the SARS-CoV-2 helicase were analyzed. Only modest impacts on nsp13-catalyzed ATP hydrolyses were observed with some compounds, most of which were analogs of the drug ebselen, not ML283. In contrast, a new molecular-beacon-based helicase assay revealed that ML283 and many ML283 analogs are potent SARS-CoV-2 helicase inhibitors. Analog potencies correlate with the binding energies predicted by modeling, which suggests that a pocket surrounded by the carboxy-terminal nsp13 RecA-like helicase motor domain might be exploitable for antiviral drug development.