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furin, paired basic amino acid cleaving enzyme

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Target not currently curated in GtoImmuPdb

Target id: 2366

Nomenclature: furin, paired basic amino acid cleaving enzyme

Family: S8: Subtilisin

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 794 15q26.1 FURIN furin, paired basic amino acid cleaving enzyme
Mouse 1 793 7 45.65 cM Furin furin (paired basic amino acid cleaving enzyme)
Rat 1 793 1q31 Furin furin (paired basic amino acid cleaving enzyme)
Previous and Unofficial Names Click here for help
dibasic-processing enzyme | Fur | PACE | PCSK3 | prohormone convertase 3 | proprotein convertase subtilisin/kexin type 3 | SPC1 | subtilisin pro-protein processing enzyme | furin (paired basic amino acid cleaving enzyme)
Database Links Click here for help
Specialist databases
MEROPS S08.071 (Hs)
Other databases
BRENDA
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Enzyme
KEGG Gene
OMIM
Pharos
RefSeq Nucleotide
RefSeq Protein
SynPHARM
UniProtKB
Wikipedia
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  X-ray structure of human furin in complex with the competitive inhibitor para-guanidinomethyl-Phac-R-Tle-R-Amba (MI-1148).
PDB Id:  4RYD
Ligand:  MI-1148
Resolution:  2.15Å
Species:  Human
References:  5
Enzyme Reaction Click here for help
EC Number: 3.4.21.75

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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
MI-1148 Small molecule or natural product Primary target of this compound Hs Inhibition 11.3 pKi 5
pKi 11.3 (Ki 5.5x10-12 M) [5]
phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.1 pKi 1
pKi 9.1 (Ki 8.1x10-10 M) [1]
peptide 18 [PMID: 24350995] Small molecule or natural product Click here for species-specific activity table Hs Inhibition 8.4 pKi 6
pKi 8.4 (Ki 4.3x10-9 M) [6]
furin inhibitor peptide Peptide Primary target of this compound Click here for species-specific activity table Hs Inhibition 7.6 pKi 7
pKi 7.6 (Ki 2.3x10-8 M) [7]
Inhibitor Comments
The furin inhibitor decanoyl-RVKR-chloromethylketone inhibits cleavage of SARS-CoV-2 spike glycoprotein at the furin cleavage site, and this partially inhibits the capacity of the virus to infect host cells [2].
Immuno Process Associations
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 2 GO processes
GO:0032911 negative regulation of transforming growth factor beta1 production IMP
GO:1901394 positive regulation of transforming growth factor beta1 activation IDA
General Comments
Several viruses exploit the serine peptidase activity of furin to activate their envelope glycoproteins, to facilitate fusion of their membranes with host cell membranes during the infection process [3]. Specific viruses that utilise host furin include HIV-1 [4] and SARS-CoV-2 [2]. Application of furin inhibitors in vitro can block infection by these viruses, and reduce viral replicative capacity.

References

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1. Becker GL, Sielaff F, Than ME, Lindberg I, Routhier S, Day R, Lu Y, Garten W, Steinmetzer T. (2010) Potent inhibitors of furin and furin-like proprotein convertases containing decarboxylated P1 arginine mimetics. J. Med. Chem., 53 (3): 1067-75. [PMID:20038105]

2. Cheng Y-W, Chao T-L, Li C-L, Chen P-J, Chang S-Y, Yeh S-H. (2020) Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects. Cell Reports, [Epub ahead of print]. DOI: 10.1016/j.celrep.2020.108254

3. Gagnon H, Beauchemin S, Kwiatkowska A, Couture F, D'Anjou F, Levesque C, Dufour F, Desbiens AR, Vaillancourt R, Bernard S et al.. (2014) Optimization of furin inhibitors to protect against the activation of influenza hemagglutinin H5 and Shiga toxin. J. Med. Chem., 57 (1): 29-41. [PMID:24359257]

4. Hallenberger S, Bosch V, Angliker H, Shaw E, Klenk HD, Garten W. (1992) Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gp160. Nature, 360 (6402): 358-61. [PMID:1360148]

5. Hardes K, Becker GL, Lu Y, Dahms SO, Köhler S, Beyer W, Sandvig K, Yamamoto H, Lindberg I, Walz L et al.. (2015) Novel Furin Inhibitors with Potent Anti-infectious Activity. ChemMedChem, 10 (7): 1218-31. [PMID:25974265]

6. Kwiatkowska A, Couture F, Levesque C, Ly K, Desjardins R, Beauchemin S, Prahl A, Lammek B, Neugebauer W, Dory YL et al.. (2014) Design, synthesis, and structure-activity relationship studies of a potent PACE4 inhibitor. J. Med. Chem., 57 (1): 98-109. [PMID:24350995]

7. Shiryaev SA, Remacle AG, Ratnikov BI, Nelson NA, Savinov AY, Wei G, Bottini M, Rega MF, Parent A, Desjardins R et al.. (2007) Targeting host cell furin proprotein convertases as a therapeutic strategy against bacterial toxins and viral pathogens. J. Biol. Chem., 282 (29): 20847-53. [PMID:17537721]

How to cite this page

S8: Subtilisin: furin, paired basic amino acid cleaving enzyme. Last modified on 25/09/2020. Accessed on 30/11/2020. IUPHAR/BPS Guide to PHARMACOLOGY, http://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2366.