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CoV Papain-like protease

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Target not currently curated in GtoImmuPdb

Target id: 3132

Nomenclature: CoV Papain-like protease

Family: Coronavirus (CoV) proteins

Previous and Unofficial Names Click here for help
non-structural protein 3 | NS3 | nsp3 | PL-PRO
Database Links Click here for help
UniProtKB

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Inhibitors
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Ligand Sp. Action Value Parameter Reference
ebselen Small molecule or natural product SARS-CoV-2 Inhibition 5.7 pIC50 6
pIC50 5.7 (IC50 2x10-6 M) [6]
GRL-0617 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 5.6 pIC50 3
pIC50 5.6 (IC50 2.4x10-6 M) [3]
Inhibitor Comments
GRL-0617 inhibits PL-Pro from SARS-CoV with an IC50 of 600 nM [5].
General Comments
SARS-CoV-2 papain-like protease (PL-pro) is translated as part of the virus' replicase polyprotein 1a/1ab, and is also know as non-structural protein 3. It does not have a gene of its own, but we have curated it as a discrete entity to help make evolving biological and pharmacological information more accessible. PL-pro is an 1945 amino acid protein, comprising aa 819-2763 of the replicase polyprotein (PRO_0000449637 in UniProt, RefSeq protein YP_009742610). Both Mpro (3CL-pro; the other essential SARS-CoV-2 protease) and PL-pro are autocatalytically processed from the replicase polyprotein. Coronavirus PL-pros belong to the peptidase clan CA (family C16). The active site contains a classic catalytic Cys-His-Asp consensus sequence.

PL-pro is a multi-functional protein that catalyses cleavages located at the N-terminus of the replicase polyprotein. Based on similarity with SARS-CoV PL-pro, SARS-CoV-2 PL-pro likely has deubiquitinating [1] and deISGylating [4] activities, participates in assembly of new viral particles, and contributes to virally-mediated inhibition of the host innate immune type I interferon response [2]. Existing evidence of the druggability of SARS-CoV PL-pro [5] has led to investigation of the SARS-CoV-2 homologue as a molecular target for COVID-19 therapy [3].

References

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1. Barretto N, Jukneliene D, Ratia K, Chen Z, Mesecar AD, Baker SC. (2005) The papain-like protease of severe acute respiratory syndrome coronavirus has deubiquitinating activity. J. Virol., 79 (24): 15189-98. [PMID:16306590]

2. Devaraj SG, Wang N, Chen Z, Chen Z, Tseng M, Barretto N, Lin R, Peters CJ, Tseng CT, Baker SC et al.. (2007) Regulation of IRF-3-dependent innate immunity by the papain-like protease domain of the severe acute respiratory syndrome coronavirus. J. Biol. Chem., 282 (44): 32208-21. [PMID:17761676]

3. Freitas BT, Durie IA, Murray J, Longo JE, Miller HC, Crich D, Hogan RJ, Tripp RA, Pegan SD. (2020) Characterization and Noncovalent Inhibition of the Deubiquitinase and deISGylase Activity of SARS-CoV-2 Papain-Like Protease. ACS Infect Dis, [Epub ahead of print]. DOI: 10.1021/acsinfecdis.0c00168 [PMID:32428392]

4. Lindner HA, Lytvyn V, Qi H, Lachance P, Ziomek E, Ménard R. (2007) Selectivity in ISG15 and ubiquitin recognition by the SARS coronavirus papain-like protease. Arch. Biochem. Biophys., 466 (1): 8-14. [PMID:17692280]

5. Ratia K, Pegan S, Takayama J, Sleeman K, Coughlin M, Baliji S, Chaudhuri R, Fu W, Prabhakar BS, Johnson ME et al.. (2008) A noncovalent class of papain-like protease/deubiquitinase inhibitors blocks SARS virus replication. Proc. Natl. Acad. Sci. U.S.A., 105 (42): 16119-24. [PMID:18852458]

6. Węglarz-Tomczak E, Tomczak JM, Talma M, Brul S. (2020) Ebselen as a highly active inhibitor of PLProCoV2. bioRxiv, Preprint. DOI: 10.1101/2020.05.17.100768

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