8IGN

Crystal structure of SARS-CoV-2 main protease in complex with RAY1216

8IGN の概要

• エントリーDOI: 10.2210/pdb8ign/pdb
• 分子名称: 3C-like proteinase nsp5, Leritrelvir bound form (3 entities in total)
• 機能のキーワード: sars-cov-2, nsp5, main protease, coronavirus, protease inhibitor, alpha-ketoamide inhibitor, peptidomimetic inhibitor, viral protein
• 由来する生物種: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• タンパク質・核酸の鎖数: 2
• 化学式量合計: 68934.54

構造登録者

Huang, X.,Zhou, B.,Xu, J.,Yang, Z.,Zhong, N.,Xiong, X. (登録日: 2023-02-21, 公開日: 2023-04-05, 最終更新日: 2026-01-28)

主引用文献

Chen, X.,Huang, X.,Ma, Q.,Kuzmic, P.,Zhou, B.,Zhang, S.,Chen, J.,Xu, J.,Liu, B.,Jiang, H.,Zhang, W.,Yang, C.,Wu, S.,Huang, J.,Li, H.,Long, C.,Zhao, X.,Xu, H.,Sheng, Y.,Guo, Y.,Niu, C.,Xue, L.,Xu, Y.,Liu, J.,Zhang, T.,Spencer, J.,Zhu, Z.,Deng, W.,Chen, X.,Chen, S.H.,Zhong, N.,Xiong, X.,Yang, Z.
Preclinical evaluation of the SARS-CoV-2 M pro inhibitor RAY1216 shows improved pharmacokinetics compared with nirmatrelvir.
Nat Microbiol, 9:1075-1088, 2024

PubMed Abstract: Although vaccines are available for SARS-CoV-2, antiviral drugs such as nirmatrelvir are still needed, particularly for individuals in whom vaccines are less effective, such as the immunocompromised, to prevent severe COVID-19. Here we report an α-ketoamide-based peptidomimetic inhibitor of the SARS-CoV-2 main protease (M), designated RAY1216. Enzyme inhibition kinetic analysis shows that RAY1216 has an inhibition constant of 8.4 nM and suggests that it dissociates about 12 times slower from M compared with nirmatrelvir. The crystal structure of the SARS-CoV-2 M:RAY1216 complex shows that RAY1216 covalently binds to the catalytic Cys145 through the α-ketoamide group. In vitro and using human ACE2 transgenic mouse models, RAY1216 shows antiviral activities against SARS-CoV-2 variants comparable to those of nirmatrelvir. It also shows improved pharmacokinetics in mice and rats, suggesting that RAY1216 could be used without ritonavir, which is co-administered with nirmatrelvir. RAY1216 has been approved as a single-component drug named 'leritrelvir' for COVID-19 treatment in China.

PubMed: 38553607
DOI: 10.1038/s41564-024-01618-9

実験手法

X-RAY DIFFRACTION (2.02 Å)