Discovery of Chlorofluoroacetamide-Based Covalent Inhibitors for SARS-CoV-2 3CL Protease

• Published in: bioRxiv
• 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: Paper
• Language: Japanese
• Published: Cold Spring Harbor Laboratory 06.06.2022
• Edition: 1.1
• Subjects: Biochemistry
• ISSN: 2692-8205
• DOI: 10.1101/2022.06.05.494897

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