Nidoviral papain-like protease (PLPro)

Nidoviral papain-like proteases are viral cysteine proteases encoded by nidoviruses—including all coronaviruses—that play a critical role in the cleavage of the N-terminal region of large viral polyproteins during virus replication. This processing is essential for generating functional nonstructural proteins required for RNA synthesis. The best-studied examples are found in SARS-CoV, SARS-CoV‑2, and MERS-CoV. In addition to their primary role as endopeptidases cleaving specific sites within the replicative polyprotein, these enzymes also function as deubiquitinating enzymes (DUBs) and deISGylating enzymes, removing ubiquitin or ISG15 modifications from host cell proteins. These activities help viruses evade innate immune responses by interfering with key signaling pathways involved in antiviral defense. Structurally, nidoviral papain-like proteases share a fold similar to cellular papain but have unique features such as an intact zinc-binding motif and a specialized substrate recognition site that accommodates both peptide bonds within the viral polyprotein and isopeptide bonds linking ubiquitin/ISG15 to target proteins. The active site typically contains a catalytic triad composed of cysteine, histidine, and aspartate residues. Because they are essential for both viral maturation and suppression of host immunity—and because their structure differs sufficiently from most human homologues—these enzymes are considered high-priority targets for antiviral drug development against diseases like COVID‑19. Several small-molecule inhibitors have been identified preclinically; however, none have yet reached widespread clinical use. Alternative names include "papain-like proteinase," "PLPro," "PLP," or more specifically "coronavirus papain-like peptidase." When multiple domains exist within one virus genome they may be referred to numerically (e.g., PLP1/PLP2). Their molecular classification places them among clan CA cysteine endopeptidases per MEROPS nomenclature.

Other names

Papain-like proteaseCoronavirus papain-like peptidasePLProPLPPapain-like proteinaseDeubiquitinating enzyme of coronaviruses

Inhibition of the cysteine protease activity to block viral polyprotein processing, thereby halting viral replication; Inhibition of deubiquitinase/deISGylating activity to restore or enhance host antiviral immune responses