2. Academic Validation
  3. Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease

Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for Severe Acute Respiratory Syndrome Coronavirus 2 3CL Protease

  • J Med Chem. 2022 Oct 27;65(20):13852-13865. doi: 10.1021/acs.jmedchem.2c01081.
Yuya Hirose 1,  Naoya Shindo 1,  Makiko Mori 1,  Satsuki Onitsuka 1,  Hikaru Isogai 1,  Rui Hamada 1,  Tadanari Hiramoto 1,  Jinta Ochi 1,  Daisuke Takahashi 1,  Tadashi Ueda 1,  Jose M M Caaveiro 1,  Yuya Yoshida 1,  Shigehiro Ohdo 1,  Naoya Matsunaga 1,  Shinsuke Toba 2 3,  Michihito Sasaki 2,  Yasuko Orba 2,  Hirofumi Sawa 2 4 5,  Akihiko Sato 2 3,  Eiji Kawanishi 1,  Akio Ojida 1
Affiliations

Affiliations

  • 1 Graduate School of Pharmaceutical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka812-8582, Japan.
  • 2 International Institute for Zoonosis Control, Hokkaido University, North 20, West 10 Kita-ku, Sapporo001-0020, Japan.
  • 3 Drug Discovery and Disease Research Laboratory, Shionogi & Co. Ltd., 3-1-1 Futaba-cho, Toyonaka, Osaka561-0825, Japan.
  • 4 One Health Research Center, Hokkaido University, North 18, West 9 Kita-ku, Sapporo060-0818, Japan.
  • 5 Global Virus Network, 725 West Lombard St. Room S413, Baltimore, Maryland21201, United States.
PMID: 36229406 DOI: 10.1021/acs.jmedchem.2c01081
Abstract

The coronavirus disease 2019 (COVID-19) pandemic has necessitated the development of Antiviral agents against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). 3C-like protease (3CLpro) is a promising target for COVID-19 treatment. Here, we report a new class of covalent inhibitors of 3CLpro that possess chlorofluoroacetamide (CFA) as a cysteine-reactive warhead. Based on an aza-peptide scaffold, we synthesized a series of CFA derivatives in enantiopure form and evaluated their biochemical efficiency. The data revealed that 8a (YH-6) with the R configuration at the CFA unit strongly blocks SARS-CoV-2 replication in infected cells, and its potency is comparable to that of nirmatrelvir. X-ray structural analysis showed that YH-6 formed a covalent bond with Cys145 at the catalytic center of 3CLpro. The strong Antiviral activity and favorable pharmacokinetic properties of YH-6 suggest its potential as a lead compound for the treatment of COVID-19.

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