8DZ2

Crystal Structure of SARS-CoV-2 Main protease in complex with Nirmatrelvir

8DZ2 の概要

• エントリーDOI: 10.2210/pdb8dz2/pdb
• 分子名称: 3C-like proteinase nsp5, (1R,2S,5S)-N-{(1E,2S)-1-imino-3-[(3S)-2-oxopyrrolidin-3-yl]propan-2-yl}-6,6-dimethyl-3-[3-methyl-N-(trifluoroacetyl)-L-valyl]-3-azabicyclo[3.1.0]hexane-2-carboxamide, DIMETHYL SULFOXIDE, ... (4 entities in total)
• 機能のキーワード: mpro, 3cl, covid, sars-cov-2 ensitrelvir, nirmatrelvir, viral protein, hydrolase-inhibitor complex, hydrolase/inhibitor
• 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: 68888.58

構造登録者

Noske, G.D.,Oliva, G.,Godoy, A.S. (登録日: 2022-08-06, 公開日: 2022-10-05, 最終更新日: 2024-11-06)

主引用文献

Noske, G.D.,de Souza Silva, E.,de Godoy, M.O.,Dolci, I.,Fernandes, R.S.,Guido, R.V.C.,Sjo, P.,Oliva, G.,Godoy, A.S.
Structural basis of nirmatrelvir and ensitrelvir activity against naturally occurring polymorphisms of the SARS-CoV-2 main protease.
J.Biol.Chem., 299:103004-103004, 2023

PubMed Abstract: SARS-CoV-2 is the causative agent of COVID-19. The main viral protease (M) is an attractive target for antivirals. The clinically approved drug nirmatrelvir and the clinical candidate ensitrelvir have so far showed great potential for treatment of viral infection. However, the broad use of antivirals is often associated with resistance generation. Herein, we enzymatically characterized 14 naturally occurring M polymorphisms that are close to the binding site of these antivirals. Nirmatrelvir retained its potency against most polymorphisms tested, while mutants G143S and Q189K were associated with diminished inhibition constants. For ensitrelvir, diminished inhibition constants were observed for polymorphisms M49I, G143S, and R188S, but not for Q189K, suggesting a distinct resistance profile between inhibitors. In addition, the crystal structures of selected polymorphisms revealed interactions that were critical for loss of potency. In conclusion, our data will assist the monitoring of potential resistant strains, support the design of combined therapy, as well as assist the development of the next generation of M inhibitors.

PubMed: 36775130
DOI: 10.1016/j.jbc.2023.103004

実験手法

X-RAY DIFFRACTION (2.129 Å)