Penicillin Derivatives Inhibit the SARS-CoV‑2 Main Protease by Reaction with Its Nucleophilic Cysteine

The
SARS-CoV-2 main
protease (Mpro) is a medicinal chemistry
target for COVID-19 treatment. Given the clinical efficacy of β-lactams
as inhibitors of bacterial nucleophilic enzymes, they are of interest
as inhibitors of viral nucleophilic serine and cysteine proteases.
We describe the synthesis of penicillin derivatives which are potent
Mpro inhibitors and investigate their mechanism of inhibition
using mass spectrometric and crystallographic analyses. The results
suggest that β-lactams have considerable potential as Mpro inhibitors via a mechanism involving reaction with the
nucleophilic cysteine to form a stable acyl–enzyme complex
as shown by crystallographic analysis. The results highlight the potential
for inhibition of viral proteases employing nucleophilic catalysis
by β-lactams and related acylating agents.