Non-Covalent Inhibitors of SARS-CoV‑2 Papain-Like Protease (PLpro): In Vitro and In Vivo Antiviral Activity

The SARS-CoV-2 papain-like
protease (PLpro), essential
for viral
processing and immune response disruption, is a promising target for
treating acute infection of SARS-CoV-2. To date, there have been no
reports of PLpro inhibitors with both submicromolar potency and animal
model efficacy. To address the challenge of PLpro’s featureless
active site, a noncovalent inhibitor library with over 50 new analogs
was developed, targeting the PLpro active site by modulating the BL2-loop
and engaging the BL2-groove. Notably, compounds 42 and 10 exhibited strong antiviral effects and were further analyzed
pharmacokinetically. 10, in particular, showed a significant
lung accumulation, up to 12.9-fold greater than plasma exposure, and
was effective in a mouse model of SARS-CoV-2 infection, as well as
against several SARS-CoV-2 variants. These findings highlight the
potential of 10 as an in vivo chemical probe for studying
PLpro inhibition in SARS-CoV-2 infection.