9XYZ

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) E166V Mutant

9XYZ の概要

• エントリーDOI: 10.2210/pdb9xyz/pdb
• 分子名称: 3C-like proteinase nsp5 (2 entities in total)
• 機能のキーワード: protease, sars-cov-2, mpro, apo, covid-19, viral protein, hydrolase
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2
• タンパク質・核酸の鎖数: 1
• 化学式量合計: 33667.43

構造登録者

Kohaal, N.,Wang, J.,Chen, Y. (登録日: 2025-08-26, 公開日: 2026-01-21, 最終更新日: 2026-02-11)

主引用文献

Cai, Z.,Kohaal, N.,Georgiou, K.,Liang, X.,Chi, X.,Tan, H.,Tan, B.,Li, K.,Fan, G.,Lambrinidis, G.,Kolocouris, A.,Deng, X.,Chen, Y.,Wang, J.
Structure-Based Design of Covalent SARS-CoV‐2 Main Protease Inhibitors Targeting the Nirmatrelvir-Resistant E166 Mutants.
Jacs Au, 6:233-244, 2026

PubMed Abstract: The COVID-19 pandemic spurred the rapid development of nirmatrelvir, a main protease (M) inhibitor now widely prescribed as part of Paxlovid (nirmatrelvir plus ritonavir). However, increasing use has raised concerns about drug resistance. Resistance selection studies have identified multiple M mutations, with E166V emerging as a particularly resistant variant. Sequencing data from COVID-19 patients confirms E166V as a clinically relevant mutation, and importantly, this substitution also confers cross-resistance to several next-generation M inhibitors under development. In response, this study reports the rational design of inhibitors active against nirmatrelvir-resistant E166V/A mutants. The lead candidate, , shows potent inhibition of both wild-type M and the E166V/A mutants. Structural studies and molecular dynamics simulations reveal that forms stable complexes with wild-type and mutant proteases, consistent with its potent enzymatic and antiviral activity. Together, these findings position as a promising next-generation M inhibitor capable of overcoming clinically relevant nirmatrelvir resistance.

PubMed: 41614164
DOI: 10.1021/jacsau.5c01178

実験手法

X-RAY DIFFRACTION (2.42 Å)