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

Kneller, Daniel W.; Li, Hui; Phillips, Gwyndalyn; Weiss, Kevin L.; Zhang, Qiu; Arnould, Mark A.; Jonsson, Colleen B.; Surendranathan, Surekha; Parvathareddy, Jyothi; Blakeley, Matthew P.; Coates, Leighton; Louis, John M.; Bonnesen, Peter V.; Kovalevsky, Andrey

doi:10.1038/s41467-022-29915-z

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

Journal Article · Wed Apr 27 00:00:00 UTC 2022 · Nature Communications

DOI:https://doi.org/10.1038/s41467-022-29915-z· OSTI ID:1865746

^[1]; ^[2]; ^[1]; ^[1]; ^[1]; ^[2]; Jonsson, Colleen B. ^[3]; Surendranathan, Surekha ^[4]; Parvathareddy, Jyothi ^[4]; ^[5]; ^[6]; ^[7]; ^[2]; ^[1]

Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Center for Nanophase Materials Sciences (CNMS)
Univ. of Tennessee Health Science Center, Memphis, TN (United States). Inst. for the Study of Host-Pathogen Systems; Univ. of Tennessee Health Science Center, Memphis, TN (United States). Regional Biocontainment Lab.
Univ. of Tennessee Health Science Center, Memphis, TN (United States). Regional Biocontainment Lab.
Inst. Laue-Langevin (ILL), Grenoble (France)
Oak Ridge National Lab. (ORNL), Oak Ridge, TN (United States). Second Target Station
National Institutes of Health (NIH), Bethesda, MD (United States). National Inst. of Diabetes and Digestive and Kidney Diseases, Lab. of Chemical Physics

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 M^pro/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 M^pro active site adapt to the inhibitor, which appears to be an intrinsic property of M^pro. 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.

View Accepted Manuscript (DOE)

Research Organization:: Oak Ridge National Laboratory (ORNL), Oak Ridge, TN (United States)

Sponsoring Organization:: USDOE Office of Science (SC), Biological and Environmental Research (BER)

Grant/Contract Number:: AC05-00OR22725

OSTI ID:: 1865746

Journal Information:: Nature Communications, Journal Name: Nature Communications Journal Issue: 1 Vol. 13; ISSN 2041-1723

Publisher:: Nature Publishing GroupCopyright Statement

Country of Publication:: United States

Language:: English

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