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

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.