7MBI

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

Summary for 7MBI

• Entry DOI: 10.2210/pdb7mbi/pdb
• Descriptor: 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)
• Functional Keywords: viral protein, hydrolase-hydrolase inhibitor complex, hydrolase/hydrolase inhibitor
• Biological source: Severe acute respiratory syndrome coronavirus 2 (2019-nCoV, SARS-CoV-2)
• Total number of polymer chains: 4
• Total formula weight: 137349.62

Authors

Khan, M.B.,Lu, J.,Young, H.S.,Lemieux, M.J. (deposition date: 2021-03-31, release date: 2021-07-21, Last modification date: 2024-11-20)

Primary citation

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

Experimental method

X-RAY DIFFRACTION (2.15 Å)