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Target intelligence / Profile preview
Papain-like protease of SARS-CoV-2 (PLpro)
- Target
- PLpro
- Molecular classification
- Enzyme, Cysteine protease, Viral protease
01
Overview
Papain-like protease of SARS-CoV-2 (PLpro) is a domain of the non-structural protein 3 (Nsp3) and acts as a cysteine protease essential for coronavirus replication and pathogenesis. It processes viral polyproteins pp1a and pp1ab at three specific cleavage sites to generate nonstructural proteins necessary for assembly of the replication–transcription complex. In addition to its role in viral polyprotein maturation, PLpro removes ubiquitin and ISG15 from host proteins, antagonizing host innate immune responses and facilitating viral evasion of immunity. Due to these critical roles, PLpro is considered a promising antiviral drug target and several small-molecule inhibitors are being developed to block its activity.
- Other names
- SARS-CoV-2 papain-like proteasePLproNon-structural protein 3 protease domainNsp3 papain-like protease domain
02
Mechanism of action
Inhibition of protease activity, preventing processing of viral polyproteins and thus blocking viral replication - Inhibition of deubiquitinase and deISGylase activities to enhance antiviral immune response
03
Biological functions
Proteolytic cleavage of viral polyproteins (pp1a and pp1ab) to release essential nonstructural proteins (Nsp1, Nsp2, Nsp3)Deubiquitination (removal of ubiquitin from host proteins)De-ISGylation (removal of ISG15 from host proteins)Evasion/modulation of host innate immune response
04
Disease associations
Infection
05
Safety considerations
Potential off-target effects due to similarity with human deubiquitinasesImmune-related adverse effects from altering host protein modification pathways
06
Interacting drugs
GRL0617 and derivatives
1 more in the full profile.
07
Biomarkers
Viral RNA levels (as a surrogate for PLpro inhibitor efficacy)Activity of ISG15 and ubiquitin conjugates (to monitor host immune pathway modulation)
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