Covalent narlaprevir- and boceprevir-derived hybrid inhibitors of SARS-CoV-2 main protease

Daniel W. Kneller, Hui Li, Gwyndalyn Phillips, Kevin L. Weiss, Qiu Zhang, Mark A. Arnould, Colleen B. Jonsson, Surekha Surendranathan, Jyothi Parvathareddy, Matthew P. Blakeley, Leighton Coates, John M. Louis, Peter V. Bonnesen () and Andrey Kovalevsky ()
Additional contact information
Daniel W. Kneller: Oak Ridge National Laboratory
Hui Li: Oak Ridge National Laboratory
Gwyndalyn Phillips: Oak Ridge National Laboratory
Kevin L. Weiss: Oak Ridge National Laboratory
Qiu Zhang: Oak Ridge National Laboratory
Mark A. Arnould: Oak Ridge National Laboratory
Colleen B. Jonsson: University of Tennessee Health Science Center
Surekha Surendranathan: The University of Tennessee Health Science Center
Jyothi Parvathareddy: The University of Tennessee Health Science Center
Matthew P. Blakeley: Institut Laue–Langevin
Leighton Coates: Oak Ridge National Laboratory
John M. Louis: National Institutes of Health, DHHS
Peter V. Bonnesen: Oak Ridge National Laboratory
Andrey Kovalevsky: Oak Ridge National Laboratory

Nature Communications, 2022, vol. 13, issue 1, 1-11

Abstract: Abstract Emerging SARS-CoV-2 variants continue to threaten the effectiveness of COVID-19 vaccines, and small-molecule antivirals can provide an important therapeutic treatment option. The viral main protease (Mpro) is critical for virus replication and thus is considered an attractive drug target. We performed the design and characterization of three covalent hybrid inhibitors BBH-1, BBH-2 and NBH-2 created by splicing components of hepatitis C protease inhibitors boceprevir and narlaprevir, and known SARS-CoV-1 protease inhibitors. A joint X-ray/neutron structure of the Mpro/BBH-1 complex demonstrates that a Cys145 thiolate reaction with the inhibitor’s keto-warhead creates a negatively charged oxyanion. Protonation states of the ionizable residues in the Mpro active site adapt to the inhibitor, which appears to be an intrinsic property of Mpro. Structural comparisons of the hybrid inhibitors with PF-07321332 reveal unconventional F···O interactions of PF-07321332 with Mpro which may explain its more favorable enthalpy of binding. BBH-1, BBH-2 and NBH-2 exhibit comparable antiviral properties in vitro relative to PF-07321332, making them good candidates for further design of improved antivirals.

Date: 2022
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DOI: 10.1038/s41467-022-29915-z

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