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

Haozhou Tan, Yanmei Hu, Prakash Jadhav, Bin Tan, Jun Wang

Research output: Contribution to journalReview articlepeer-review

65 Scopus citations


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 PLproinhibitors since the beginning of the pandemic. Encouraging progress includes the design of non-covalent PLproinhibitors with favorable pharmacokinetic properties and the first-in-class covalent PLproinhibitors. In addition, we offer our opinion on the knowledge gaps that need to be filled to advance PLproinhibitors to the clinic.

Original languageEnglish (US)
Pages (from-to)7561-7580
Number of pages20
JournalJournal of Medicinal Chemistry
Issue number11
StatePublished - Jun 9 2022
Externally publishedYes

ASJC Scopus subject areas

  • Molecular Medicine
  • Drug Discovery


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