7MBI

Structure of SARS-CoV2 3CL protease covalently bound to peptidomimetic inhibitor

7MBI の概要

• エントリーDOI: 10.2210/pdb7mbi/pdb
• 分子名称: 3C-like proteinase, 4-methoxy-N-[(2S)-4-methyl-1-oxo-1-({(2S)-3-oxo-1-[(3S)-2-oxopiperidin-3-yl]butan-2-yl}amino)pentan-2-yl]-1H-indole-2-carboxamide, 2,4,6-trimethylpyridine-3-carboxylic acid, ... (4 entities in total)
• 機能のキーワード: viral protein, hydrolase-hydrolase inhibitor complex, hydrolase/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: 4
• 化学式量合計: 137349.62

構造登録者

Khan, M.B.,Lu, J.,Young, H.S.,Lemieux, M.J. (登録日: 2021-03-31, 公開日: 2021-07-21, 最終更新日: 2024-11-20)

主引用文献

Bai, B.,Belovodskiy, A.,Hena, M.,Kandadai, A.S.,Joyce, M.A.,Saffran, H.A.,Shields, J.A.,Khan, M.B.,Arutyunova, E.,Lu, J.,Bajwa, S.K.,Hockman, D.,Fischer, C.,Lamer, T.,Vuong, W.,van Belkum, M.J.,Gu, Z.,Lin, F.,Du, Y.,Xu, J.,Rahim, M.,Young, H.S.,Vederas, J.C.,Tyrrell, D.L.,Lemieux, M.J.,Nieman, J.A.
Peptidomimetic alpha-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability.
J.Med.Chem., 65:2905-2925, 2022

PubMed Abstract: Recurring coronavirus outbreaks, such as the current COVID-19 pandemic, establish a necessity to develop direct-acting antivirals that can be readily administered and are active against a broad spectrum of coronaviruses. Described in this Article are novel α-acyloxymethylketone warhead peptidomimetic compounds with a six-membered lactam glutamine mimic in P1. Compounds with potent SARS-CoV-2 3CL protease and viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds , , and displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of with SARS-CoV-2 3CL protease confirmed the formation of a covalent adduct. α-Acyloxymethylketone compounds also exhibited antiviral activity against an alphacoronavirus and non-SARS betacoronavirus strains with similar potency and a better selectivity index than remdesivir. These findings demonstrate the potential of the substituted heteroaromatic and aliphatic α-acyloxymethylketone warheads as coronavirus inhibitors, and the described results provide a basis for further optimization.

PubMed: 34242027
DOI: 10.1021/acs.jmedchem.1c00616

実験手法

X-RAY DIFFRACTION (2.15 Å)