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

Abstract

The RNA-dependent RNA polymerase (RdRp), 3C-like protease (3CLpro), and papain-like protease (PLpro) 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 3CLproinhibitors. However, the mutations causing drug resistance have been observed in RdRp and 3CLprofrom 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 discovered a series of novel potent non-covalent PLproinhibitors with remarkable in vitro potency and in vivo PK properties. The co-crystal structures of PLprowith leads revealed that the residues E164 and Q269 around the S2 site are critical for improving the inhibitor's potency. The lead compound GZNL-P36 not only inhibited SARS-CoV-2 and its variants at the cellular level with EC50ranging from 58.2 nM to 306.2 nM, but also inhibited HCoV-NL63 and HCoV-229E with EC50of 81.6 nM and 2.66 μM, respectively. Oral administration of the compound resulted 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 PLproinhibitor is a promising SARS-CoV-2 therapy.