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

• Published in: Journal of medicinal chemistry Vol. 65; no. 20; pp. 13852 - 13865
• Main Authors: Hirose, Yuya, Shindo, Naoya, Mori, Makiko, Onitsuka, Satsuki, Isogai, Hikaru, Hamada, Rui, Hiramoto, Tadanari, Ochi, Jinta, Takahashi, Daisuke, Ueda, Tadashi, Caaveiro, Jose M. M., Yoshida, Yuya, Ohdo, Shigehiro, Matsunaga, Naoya, Toba, Shinsuke, Sasaki, Michihito, Orba, Yasuko, Sawa, Hirofumi, Sato, Akihiko, Kawanishi, Eiji, Ojida, Akio
• Format: Journal Article
• Language: English
• Published: WASHINGTON American Chemical Society 27.10.2022; Amer Chemical Soc
• Subjects: Chemistry, Medicinal; Life Sciences & Biomedicine; Pharmacology & Pharmacy; Science & Technology; ROUTE; ACID
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.2c01081

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.