9XZ6

Crystal Structure of SARS-CoV-2 Main Protease (Mpro) in complex with Jun13699

This is a non-PDB format compatible entry.

Summary for 9XZ6

• Entry DOI: 10.2210/pdb9xz6/pdb
• Descriptor: 3C-like proteinase nsp5, methyl {(2S)-1-[(1R,2S,5S)-6,6-dimethyl-2-{[(2S)-4-(methylsulfanyl)-1-oxobutan-2-yl]carbamoyl}-3-azabicyclo[3.1.0]hexan-3-yl]-3,3-dimethyl-1-oxobutan-2-yl}carbamate (3 entities in total)
• Functional Keywords: protease, sars-cov-2, mpro, apo, covid-19, viral protein, hydrolase
• Biological source: Severe acute respiratory syndrome coronavirus 2
• Total number of polymer chains: 1
• Total formula weight: 34267.13

Authors

Kohaal, N.,Lewandowski, E.M.,Wang, J.,Chen, Y. (deposition date: 2025-08-26, release date: 2026-01-21, Last modification date: 2026-02-11)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.47 Å)