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 (M pro ) 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 M pro 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.
【초록키워드】 Antiviral, antivirals, SARS-CoV-2 variant, protease, in vitro, SARS-CoV-1, protease inhibitors, Protease inhibitor, COVID-19 vaccines, Hepatitis, comparison, Effectiveness, hepatitis C, drug target, virus replication, PF-07321332, inhibitor, Critical, binding, boceprevir, Interaction, antiviral property, narlaprevir, active site, characterization, reaction, complex, residue, M pro, candidate, relative, Cys145, component, Therapeutic treatment, joint, intrinsic, performed, appear, comparable, explain, Protonation, 【제목키워드】 protease, inhibitors of SARS-CoV-2,