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
  • 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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