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.
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