Discovery of orally bioavailable SARS-CoV-2 papain-like protease inhibitor as a potential treatment for COVID-19.

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CL ^pro ), and papain-like protease (PL ^pro ) are pivotal components in the viral life cycle of SARS-CoV-2, presenting as promising therapeutic targets. Currently, all FDA-approved antiviral drugs against SARS-CoV-2 are RdRp or 3CL ^pro inhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CL ^pro from SARS-CoV-2, which makes it necessary to develop antivirals with novel mechanisms. Through the application of a structure-based drug design (SBDD) approach, we discover a series of novel potent non-covalent PL ^pro inhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PL ^pro with lead compounds reveal that the residues D164 and Q269 around the S2 site are critical for improving the inhibitor's potency. The lead compound GZNL-P36 not only inhibits SARS-CoV-2 and its variants at the cellular level with EC ₅₀ ranging from 58.2 nM to 306.2 nM, but also inhibits HCoV-NL63 and HCoV-229E with EC ₅₀ of 81.6 nM and 2.66 μM, respectively. Oral administration of the GZNL-P36 results in significantly improved survival and notable reductions in lung viral loads and lesions in SARS-CoV-2 infection mouse model, consistent with RNA-seq data analysis. Our results indicate that PL ^pro inhibitors represent a promising SARS-CoV-2 therapy.
Competing Interests: Competing interests: The authors declare no competing interests.
(© 2024. The Author(s).)