SARS-CoV-2 Non-structural protein 3 (Nsp3)

SARS-CoV-2 Non-structural protein 3 (Nsp3) is the largest protein in the SARS-CoV-2 proteome, serving as a critical multi-domain component of the viral replication-transcription complex (UniProt P0DTC1). It contains several distinct functional domains, most notably the papain-like protease (PLpro), which is responsible for cleaving the viral polyprotein at three specific sites to release Nsp1, Nsp2, and Nsp3 (PubMed: 32726803). Beyond its proteolytic role, Nsp3 acts as a potent antagonist of the host innate immune system through its deubiquitinating (DUB) and de-ISGylating activities (PubMed: 33035205). These activities remove ubiquitin and ISG15 modifiers from host proteins to suppress interferon signaling and other antiviral responses (PubMed: 32726803). The protein also features a macrodomain (Mac1) that possesses ADP-ribosylhydrolase activity, further contributing to viral fitness and immune evasion (PubMed: 32425134). Due to its essential roles in both viral processing and host immune modulation, Nsp3, particularly its PLpro domain, is a high-priority target for the development of antiviral therapeutics (PubMed: 32661344). Current drug discovery efforts focus on small-molecule inhibitors that can block the PLpro active site or the macrodomain to restore host immune responses and halt viral replication.

Other names

Papain-like proteasePLproMulti-domain protein 3Nsp3Replicase polyprotein 1a nsp3

Inhibition of the papain-like protease (PLpro) domain within Nsp3 prevents the proteolytic cleavage of the viral polyprotein 1a/1ab into functional non-structural proteins and blocks the protein's ability to suppress the host innate immune response by inhibiting its deubiquitinating and de-ISGylating activities (PubMed: 32726803, PubMed: 33035205).