Q1 · MEDICINE
Article
Author: Sato, Akihiko ; Ohdo, Shigehiro ; Ochi, Jinta ; Matsunaga, Naoya ; Shindo, Naoya ; Sasaki, Michihito ; Ojida, Akio ; Sawa, Hirofumi ; Hirose, Yuya ; Hamada, Rui ; Orba, Yasuko ; Caaveiro, Jose M. M. ; Onitsuka, Satsuki ; Isogai, Hikaru ; Toba, Shinsuke ; Hiramoto, Tadanari ; Mori, Makiko ; Takahashi, Daisuke ; Yoshida, Yuya ; Ueda, Tadashi ; Kawanishi, Eiji
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.