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.
Mesh Terms:
Antiviral Agents, COVID-19 Drug Treatment, Coronavirus 3C Proteases, Cysteine, Cysteine Endopeptidases, Humans, Peptide Hydrolases, Peptides, Protease Inhibitors, SARS-CoV-2
Antiviral Agents, COVID-19 Drug Treatment, Coronavirus 3C Proteases, Cysteine, Cysteine Endopeptidases, Humans, Peptide Hydrolases, Peptides, Protease Inhibitors, SARS-CoV-2
J Med Chem
Date: Oct. 27, 2022
PubMed ID: 36229406
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