In:
Angewandte Chemie, Wiley, Vol. 135, No. 41 ( 2023-10-09)
Abstract:
The main protease (M pro ) of SARS‐CoV‐2 is a well‐characterized target for antiviral drug discovery. To date, most antiviral drug discovery efforts have focused on the S4–S1′ pocket of M pro ; however, it is still unclear whether the S1′–S3′ pocket per se can serve as a new site for drug discovery. In this study, the S1′–S3′ pocket of M pro was found to differentially recognize viral peptidyl substrates. For instance, S3′ in M pro strongly favors Phe or Trp, and S1′ favors Ala. The peptidyl inhibitor D‐4–77, which possesses an α‐bromoacetamide warhead, was discovered to be a promising inhibitor of M pro , with an IC 50 of 0.95 μM and an antiviral EC 50 of 0.49 μM. The M pro /inhibitor co‐crystal structure confirmed the binding mode of the inhibitor to the S1′–S3′ pocket and revealed a covalent mechanism. In addition, D‐4–77 functions as an immune protectant and suppresses SARS‐CoV‐2 M pro ‐induced antagonism of the host NF‐κB innate immune response. These findings indicate that the S1′–S3′ pocket of SARS‐CoV‐2 M pro is druggable, and that inhibiting SARS‐CoV‐2 M pro can simultaneously protect human innate immunity and inhibit virion assembly.
Type of Medium:
Online Resource
ISSN:
0044-8249
,
1521-3757
DOI:
10.1002/ange.v135.41
DOI:
10.1002/ange.202309657
Language:
English
Publisher:
Wiley
Publication Date:
2023
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