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

J Med Chem. 2022 Feb 24;65(4):2905-2925. doi: 10.1021/acs.jmedchem.1c00616.

Bing Bai ¹ ², Alexandr Belovodskiy ¹ ², Mostofa Hena ¹ ², Appan Srinivas Kandadai ¹ ², Michael A Joyce ³ ², Holly A Saffran ³ ², Justin A Shields ³ ², Muhammad Bashir Khan ⁴, Elena Arutyunova ³ ⁴, Jimmy Lu ³ ⁴, Sardeev K Bajwa ⁴, Darren Hockman ¹ ², Conrad Fischer ⁵, Tess Lamer ⁵, Wayne Vuong ⁵, Marco J van Belkum ⁵, Zhengxian Gu ⁶, Fusen Lin ⁶, Yanhua Du ⁶, Jia Xu ⁶, Mohammad Rahim ⁷, Howard S Young ⁴, John C Vederas ⁵, D Lorne Tyrrell ¹ ³ ², M Joanne Lemieux ³ ⁴, James A Nieman ¹ ²

Affiliations

1 Li Ka Shing Applied Virology Institute, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
2 Department of Medical Microbiology and Immunology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
3 Li Ka Shing Institute of Virology, University of Alberta, Edmonton, Alberta T6G 2E1, Canada.
4 Department of Biochemistry, University of Alberta, Edmonton, Alberta T6G 2H7, Canada.
5 Department of Chemistry, University of Alberta, Edmonton, Alberta T6G 2G2, Canada.
6 WuXi AppTec (Shanghai) Co., Ltd., G Warehouse #101, No. 10 Building, #227 Meisheng Road, WaiGaoQiao Free Trade Zone, Shanghai 200131, China.
7 Rane Pharmaceuticals, Inc. 4290 91a Street NW, Edmonton, Alberta T6E 5V2, Canada.

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

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.

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