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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
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UniProtKB
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of Papain-Like Protease of SARS CoV-2 , P3221 space group.
PDB Id:  6WZU
Resolution:  1.79Å
Species:  SARS-CoV-2
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  SARS-CoV-2 papain-like protease (PLpro) bound to inhibitor XR8-24
PDB Id:  7LBS
Ligand:  XR8-24
Resolution:  2.8Å
Species:  SARS-CoV-2
References:  11
Image of receptor 3D structure from RCSB PDB
Description:  The crystal structure of Papain-Like Protease of SARS CoV-2 , C111S mutant, in complex with PLP_Snyder457 inhibitor
PDB Id:  7JIR
Ligand:  GRL-0617
Resolution:  2.09Å
Species:  SARS-CoV-2
References:  6
Image of receptor 3D structure from RCSB PDB
Description:  Structure of SARS-CoV-2 PLproC111S in complex with mouse interferon-stimulated gene 15 (ISG15) protein
PDB Id:  6YVA
Resolution:  3.18Å
Species:  SARS-CoV-2
References:  12
EC number (SARS-CoV-2)
3.4.22.46

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Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
XR8-23 Small molecule or natural product SARS-CoV-2 Binding 6.6 pKd 10
pKd 6.6 (Kd 2.35x10-7 M) [10]
XR8-24 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Binding 6.4 pKd 10
pKd 6.4 (Kd 3.72x10-7 M) [10]
compound 19 [PMID: 33979649] Small molecule or natural product SARS-CoV-2 Binding 5.6 pKd 9
pKd 5.6 (Kd 2.6x10-6 M) [9]
Description: Binding affinity by surface plasma resonance (SPR)
GRL-0617 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Binding 5.0 pKd 9
pKd 5.0 (Kd 1.08x10-5 M) [9]
Description: Binding affinity by surface plasma resonance (SPR)
XR8-23 Small molecule or natural product SARS-CoV-2 Inhibition 6.4 pIC50 10
pIC50 6.4 (IC50 3.9x10-7 M) [10]
XR8-24 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 6.4 pIC50 10
pIC50 6.4 (IC50 3.9x10-7 M) [10]
compound 19 [PMID: 33979649] Small molecule or natural product SARS-CoV-2 Inhibition 6.4 pIC50 9
pIC50 6.4 (IC50 4.4x10-7 M) [9]
Description: Inhibition of PL-pro-mediated substrate cleavage in vitro
GRL-0617 Small molecule or natural product Ligand has a PDB structure SARS-CoV Inhibition 6.2 pIC50 7
pIC50 6.2 (IC50 6x10-7 M) [7]
ebselen Small molecule or natural product SARS-CoV-2 Inhibition 5.7 pIC50 13
pIC50 5.7 (IC50 2x10-6 M) [13]
GRL-0617 Small molecule or natural product Ligand has a PDB structure SARS-CoV-2 Inhibition 5.6 – 5.6 pIC50 4,6
pIC50 5.6 – 5.6 (IC50 2.4x10-6 – 2.3x10-6 M) [4,6]
compound 4 [PMID: 33531496] Small molecule or natural product SARS-CoV-2 Inhibition 4.4 pIC50 6
pIC50 4.4 (IC50 4.32x10-5 M) [6]
View species-specific inhibitor tables
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 [2] and deISGylating [5] activities, participates in assembly of new viral particles, and contributes to virally-mediated inhibition of the host innate immune type I interferon response [3]. Existing evidence of the druggability of SARS-CoV PL-pro [7] has led to investigation of the SARS-CoV-2 homologue as a molecular target for COVID-19 therapy [4]. PL-pro contains a viral macrodomain that has been identified as druggable target [8]. Viral macrodomains are present primarily in corona, alpha, rubi, and herpes viruses, and they act to circumvent the host innate immune defence mechanism. Small molecule inhibitors that bind to this domain would be expected to compromise the pathogenicity of SARS-CoV-2 (and potentially other coronaviruses).

Inhibitors:
Several hepatitis C virus (HCV) inhibitor drugs (simeprevir, vaniprevir, paritaprevir, and grazoprevir) have been reported to inhibit PL-pro and SARS-CoV-2 infection in vitro [1]. These drugs were found to inhibit SARS-CoV-2 replication synergistically with the viral polymerase inhibitor remdesivir. The search for novel, selective PL-pro inhibitors has revealed compounds such as GRL-0617 and compound 19 [PMID: 33979649].

References

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1. Bafna K, White K, Harish B, Rosales R, Ramelot TA, Acton TB, Moreno E, Kehrer T, Miorin L, Royer CA et al.. (2021) Hepatitis C virus drugs that inhibit SARS-CoV-2 papain-like protease synergize with remdesivir to suppress viral replication in cell culture. Cell Rep,: 109133 [Epub ahead of print]. [PMID:33984267]

2. 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]

3. 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]

4. 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, 6 (8): 2099-2109. [PMID:32428392]

5. 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]

6. Osipiuk J, Azizi SA, Dvorkin S, Endres M, Jedrzejczak R, Jones KA, Kang S, Kathayat RS, Kim Y, Lisnyak VG et al.. (2021) Structure of papain-like protease from SARS-CoV-2 and its complexes with non-covalent inhibitors. Nat Commun, 12 (1): 743. [PMID:33531496]

7. 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 USA, 105 (42): 16119-24. [PMID:18852458]

8. Schuller M, Correy GJ, Gahbauer S, Fearon D, Wu T, Diaz RE, Young ID, Martins LC, Smith DH, Schulze-Gahmen U et al.. (2021) Fragment binding to the Nsp3 macrodomain of SARS-CoV-2 identified through crystallographic screening and computational docking. Science Advances, 7 (16): eabf8711 [Epub ahead of print]. DOI: 10.1126/sciadv.abf8711

9. Shan H, Liu J, Shen J, Dai J, Xu G, Lu K, Han C, Wang Y, Xu X, Tong Y et al.. (2021) Development of potent and selective inhibitors targeting the papain-like protease of SARS-CoV-2. Cell Chem Biol, [Epub ahead of print]. DOI: 10.1016/j.chembiol.2021.04.020 [PMID:33979649]

10. Shen Z, Ratia K, Cooper L, Kong D, Lee H, Kwon Y, Li Y, Alqarni S, Huang F, Dubrovskyi O et al.. (2021) Design of SARS-CoV-2 PLpro Inhibitors for COVID-19 Antiviral Therapy Leveraging Binding Cooperativity. J Med Chem, [Epub ahead of print]. DOI: 10.1021/acs.jmedchem.1c01307 [PMID:34665619]

11. Shen Z, Ratia K, Cooper L, Kong D, Lee H, Kwon Y, Li Y, Alqarni S, Huang F, Dubrovskyi O et al.. (2021) Potent, Novel SARS-CoV-2 PLpro Inhibitors Block Viral Replication in Monkey and Human Cell Cultures. bioRxiv,. [PMID:33594371]

12. Shin D, Mukherjee R, Grewe D, Bojkova D, Baek K, Bhattacharya A, Schulz L, Widera M, Mehdipour AR, Tascher G et al.. (2020) Papain-like protease regulates SARS-CoV-2 viral spread and innate immunity. Nature, 587 (7835): 657-662. [PMID:32726803]

13. 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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