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.