Review of the crystallized structures of the SARS-CoV-2 papain-like protease

In late 2019, a new CoV have caused the outbreak of deadly respiratory disease, the COVID-19 pandemic. Due to the profound impact of these viral outbreaks on public health and the economy, while several effective vaccines and antiviral drugs for SARS-CoV-2 are now available, the continuous emergence of variants highlights the ongoing need for therapeutic innovation and structural studies. The SARS-CoV-2 papain-like protease (PLpro) plays a vital role in viral replication and host immune evasion, making it a key target for therapeutic intervention. However, a series of SARS-CoV-2 PLpro structures have been published from April 1, 2020 to December 31, 2024 and it is found that a lot of literature knowledge is scattered. This article reviews the structures of these crystallized proteins, categorizes and summarizes key structural features, and compiles a wide range of existing inhibitors for preliminary analysis. Most importantly, it sorts out some known and potential cryptic binding sites, analyzing their strengths and weaknesses in conjunction with relevant literature. Through this review, we aim to provide valuable insights for future research on PLpro.