Progress and Challenges in Targeting the SARS-CoV-2 Papain-like Protease

SARS-CoV-2 is the causative agent of the COVID-19 pandemic. The approval of vaccines and small-molecule antivirals is vital in combating the pandemic. The viral polymerase inhibitors remdesivir and molnupiravir and the viral main protease inhibitor nirmatrelvir/ritonavir have been approved by the U.S. FDA. However, the emergence of variants of concern/interest calls for additional antivirals with novel mechanisms of action. The SARS-CoV-2 papain-like protease (PLpro) mediates the cleavage of viral polyprotein and modulates the host's innate immune response upon viral infection, rendering it a promising antiviral drug target. This Perspective highlights major achievements in structure-based design and high-throughput screening of SARS-CoV-2 PLpro inhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PLpro inhibitors with favorable pharmacokinetic properties and the first-in-class covalent PLpro inhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PLpro inhibitors to the clinic.

Automated summary

This article summarizes the significant progress in structure-based design and high-throughput screening of SARS-CoV-2 papain-like protease (PLpro) inhibitors since the beginning of the pandemic. Encouraging achievements include the development of non-covalent and covalent inhibitors with favorable pharmacokinetic properties. The article also identifies knowledge gaps that need to be addressed to advance PLpro inhibitors to clinical application.