期刊
NATURE COMMUNICATIONS
卷 13, 期 1, 页码 -出版社
NATURE PORTFOLIO
DOI: 10.1038/s41467-022-29915-z
关键词
-
资金
- Intramural Research Program of NIDDK, NIH
The study designed three covalent hybrid inhibitors that showed comparable antiviral activity to a known drug in vitro. The binding mechanism of these inhibitors to the viral main protease was also analyzed, providing important atomic and thermodynamic details.
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 center dot center dot center dot 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. Three covalent hybrid inhibitors of SARS-CoV-2 main protease (Mpro) have been designed and compared to Pfizer's nirmatrelvir (PF-07321332), providing atomic and thermodynamic details of their binding to the enzyme, and antiviral potency.
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