Synthesis and biological evaluation of novel peptidomimetic inhibitors of the coronavirus 3C-like protease

  • Eur J Med Chem. 2024 Feb 24:268:116263. doi: 10.1016/j.ejmech.2024.116263.
Franck Amblard  1 ,  Julia C LeCher  2 ,  Ramyani De  2 ,  Shaoman Zhou  2 ,  Peng Liu  2 ,  Shu Ling Goh  2 ,  Sijia Tao  2 ,  Dharmeshkumar Patel  2 ,  Jessica Downs-Bowen  2 ,  Keivan Zandi  2 ,  Huanchun Zhang  2 ,  Gitika Chaudhry  2 ,  Tamara McBrayer  2 ,  Michael Muczynski  3 ,  Abdullah Al-Homoudi  3 ,  Joseph Engel  3 ,  Shuiyun Lan  2 ,  Stefan G Sarafianos  2 ,  Ladislau C Kovari  3 ,  Raymond F Schinazi  4
Affiliations
  • 1. Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, GA, 30322, USA. Electronic address: [email protected].
  • 2. Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, GA, 30322, USA.
  • 3. Department of Biochemistry, Microbiology, and Immunology, Wayne State University School of Medicine, Detroit, MI, 48201, USA.
  • 4. Center for ViroScience and Cure, Laboratory of Biochemical Pharmacology, Department of Pediatrics, Emory University School of Medicine, and Children's Healthcare of Atlanta, Atlanta, GA, 30322, USA. Electronic address: [email protected].
PMID: 38432056 DOI: 10.1016/j.ejmech.2024.116263
Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), and related variants, are responsible for the devastating coronavirus disease 2019 (COVID-19) pandemic. The SARS-CoV-2 main protease (Mpro) plays a central role in the replication of the virus and represents an attractive drug target. Herein, we report the discovery of novel SARS-CoV-2 Mpro covalent inhibitors, including highly effective compound NIP-22c which displays high potency against several key variants and clinically relevant nirmatrelvir Mpro E166V mutants.

Keywords
3CL(pro); Antivirals; HCoV-OC43; Main protease; Mpro; NIP-22c; Peptides; SARS-CoV-2.
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