8Y4H

Crystal structure of SARS-Cov-2 main protease K90R mutant in complex with Bofutrelvir

Summary for 8Y4H

• Entry DOI: 10.2210/pdb8y4h/pdb
• Related PRD ID: PRD_002347
• Descriptor: 3C-like proteinase nsp5, ~{N}-[(2~{S})-3-cyclohexyl-1-oxidanylidene-1-[[(2~{S})-1-oxidanylidene-3-[(3~{S})-2-oxidanylidenepyrrolidin-3-yl]propan-2-yl]amino]propan-2-yl]-1~{H}-indole-2-carboxamide (3 entities in total)
• Functional Keywords: viral protein-inhibitor complex, viral protein
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 2
• Total formula weight: 67571.15

Authors

Guo, L.,Wang, W.W.,Zhang, J.,Li, J. (deposition date: 2024-01-30, release date: 2025-01-08, Last modification date: 2025-04-09)

Primary citation

Wang, W.,Zhou, X.,Li, W.,Zeng, P.,Guo, L.,Wang, Q.,Li, J.
Inhibitory efficacy and structural insights of Bofutrelvir against SARS-CoV-2 M pro mutants and MERS-CoV M pro.
Commun Biol, 8:493-493, 2025

PubMed Abstract: The COVID-19 pandemic has caused significant global health and economic disruption. Mutations E166N, E166R, E166N, S144A and His163A in the SARS-CoV-2 main protease (M) have been implicated in reducing the efficacy of certain antiviral treatments. Bofutrelvir, a promising inhibitor, has shown effectiveness against SARS-CoV-2 M. This study aims to evaluate the inhibitory effects of Bofutrelvir on the E166N, E166R, His163A, E166V and S144A mutants of SARS-CoV-2 M, as well as on MERS-CoV M. Our findings indicate a substantial reduction in the inhibitory potency of Bofutrelvir against these mutants and MERS-CoV, with IC values significantly higher than those for the wild-type SARS-CoV-2 M. Specifically, the E166N, E166R, E166V, S144A, and H163A mutations significantly reduce the binding affinity and inhibitory effectiveness of Bofutrelvir due to disrupted hydrogen bonds, altered binding site stability, and reduced enzyme activity. Structural analysis of the crystal complexes showed that changes in interactions at the S1 subsite in the mutants and the loss of hydrogen bonds at the S4 subsite in MERS-CoV M are critical factors contributing to the diminished inhibitory activity. These insights reveal the necessity of ongoing structural analysis to adapt therapeutic strategies.

PubMed: 40133408
DOI: 10.1038/s42003-025-07929-9

Experimental method

X-RAY DIFFRACTION (1.93 Å)