Coronaviruses papain-like proteases and their inhibitors

The multipurpose enzyme papain-like protease (PLpro) is crucial for both immune evasion and viral multiplication. The replication-transcription complex is formed when PLpro, encoded by nonstructural protein 3 (nsp3), cleaves the viral polyprotein to release nsp1 through nsp4. Furthermore, by eliminating ubiquitin and ISG15 from key immune signaling proteins, such as IRF3, STING, and MDA5, PLpro impairs host antiviral defenses by reducing type I interferon responses. The catalytic triad and several functional domains, including the flexible BL2 loop that regulates access to the viral polyprotein substrate and inhibitor, as well as the SUb1 and SUb2 binding sites for ISG15/Ub recognition, are structural features of PLpro. Due to these features, PLpro is a desirable target for both allosteric and active-site inhibition. Numerous prospective inhibitors have been identified through drug repurposing and natural product screening, supported by structural and computational analyses that highlight key interaction sites. The biological significance, structural intricacy, and therapeutic potential of PLpro as a dual-action antiviral target, which can inhibit viral replication and restore host immune function, are highlighted in this chapter.