Structure-Based Design of a Dual-Targeted Covalent Inhibitor Against Papain-like and Main Proteases of SARS-CoV‑2

The
two proteases, PLpro and Mpro, of SARS-CoV-2
are essential for replication of the virus. Using a structure-based
co-pharmacophore screening approach, we developed a novel dual-targeted
inhibitor that is equally potent in inhibiting PLpro and
Mpro of SARS-CoV-2. The inhibitor contains a novel warhead,
which can form a covalent bond with the catalytic cysteine residue
of either enzyme. The maximum rate of the covalent inactivation is
comparable to that of the most potent inhibitors reported for the
viral proteases and covalent inhibitor drugs currently in clinical
use. The covalent inhibition appears to be very specific for the viral
proteases. The inhibitor has a potent antiviral activity against SARS-CoV-2
and is also well tolerated by mice and rats in toxicity studies. These
results suggest that the inhibitor is a promising lead for development
of drugs for treatment of COVID-19.