8GWS

SARS-CoV-2 Mpro 1-302 c145a in complex with peptide 4

Summary for 8GWS

• Entry DOI: 10.2210/pdb8gws/pdb
• Descriptor: Replicase polyprotein 1ab, VAL-LYS-LEU-GLN-ALA-ILE-PHE-ARG (2 entities in total)
• Functional Keywords: mpro, substrate, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2; More
• Total number of polymer chains: 4
• Total formula weight: 68588.33

Authors

Liu, M.,Fu, Z.,Huang, H. (deposition date: 2022-09-17, release date: 2023-08-23, Last modification date: 2024-06-12)

Primary citation

Liu, M.,Li, J.,Liu, W.,Yang, Y.,Zhang, M.,Ye, Y.,Zhu, W.,Zhou, C.,Zhai, H.,Xu, Z.,Zhang, G.,Huang, H.
The S1'-S3' Pocket of the SARS-CoV-2 Main Protease Is Critical for Substrate Selectivity and Can Be Targeted with Covalent Inhibitors.
Angew.Chem.Int.Ed.Engl., 62:e202309657-e202309657, 2023

PubMed Abstract: The main protease (M ) 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 ; 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 was found to differentially recognize viral peptidyl substrates. For instance, S3' in M 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 , with an IC of 0.95 μM and an antiviral EC of 0.49 μM. The M /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 -induced antagonism of the host NF-κB innate immune response. These findings indicate that the S1'-S3' pocket of SARS-CoV-2 M is druggable, and that inhibiting SARS-CoV-2 M can simultaneously protect human innate immunity and inhibit virion assembly.

PubMed: 37609788
DOI: 10.1002/anie.202309657

Experimental method

X-RAY DIFFRACTION (2.9 Å)