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National Institute of Environmental Health Sciences

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Publication Detail

Title: Peptidomimetic α-Acyloxymethylketone Warheads with Six-Membered Lactam P1 Glutamine Mimic: SARS-CoV-2 3CL Protease Inhibition, Coronavirus Antiviral Activity, and in Vitro Biological Stability.

Authors: Bai, Bing; Belovodskiy, Alexandr; Hena, Mostofa; Kandadai, Appan Srinivas; Joyce, Michael A; Saffran, Holly A; Shields, Justin A; Khan, Muhammad Bashir; Arutyunova, Elena; Lu, Jimmy; Bajwa, Sardeev K; Hockman, Darren; Fischer, Conrad; Lamer, Tess; Vuong, Wayne; van Belkum, Marco J; Gu, Zhengxian; Lin, Fusen; Du, Yanhua; Xu, Jia; Rahim, Mohammad; Young, Howard S; Vederas, John C; Tyrrell, D Lorne; Lemieux, M Joanne; Nieman, James A

Published In J Med Chem, (2022 Feb 24)

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 in vitro viral replication inhibition were identified with low cytotoxicity and good plasma and glutathione stability. Compounds 15e, 15h, and 15l displayed selectivity for SARS-CoV-2 3CL protease over CatB and CatS and superior in vitro SARS-CoV-2 antiviral replication inhibition compared with the reported peptidomimetic inhibitors with other warheads. The cocrystallization of 15l 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 ID: 34242027 Exiting the NIEHS site

MeSH Terms: No MeSH terms associated with this publication

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