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transmembrane serine protease 2

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Target not currently curated in GtoImmuPdb

Target id: 2421

Nomenclature: transmembrane serine protease 2

Family: S1: Chymotrypsin

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 492 21q22.3 TMPRSS2 transmembrane serine protease 2
Mouse 1 490 16 57.53 cM Tmprss2 transmembrane protease, serine 2
Rat - 490 11q12 Tmprss2 transmembrane serine protease 2
Previous and Unofficial Names Click here for help
epitheliasin | plasmic transmembrane protein X | PRSS10 | transmembrane protease | transmembrane protease, serine 2
Database Links Click here for help
Specialist databases
MEROPS S01.247 (Hs)
Other databases
Alphafold O15393 (Hs), Q9JIQ8 (Mm)
BRENDA 3.4.21.-
CATH/Gene3D 3.10.250.10
ChEMBL Target CHEMBL1795140 (Hs)
Ensembl Gene ENSG00000184012 (Hs), ENSMUSG00000000385 (Mm), ENSRNOG00000001976 (Rn)
Entrez Gene 7113 (Hs), 50528 (Mm), 156435 (Rn)
Human Protein Atlas ENSG00000184012 (Hs)
KEGG Enzyme 3.4.21.-
KEGG Gene hsa:7113 (Hs), mmu:50528 (Mm), rno:156435 (Rn)
OMIM 602060 (Hs)
Pharos O15393 (Hs)
RefSeq Nucleotide NM_005656 (Hs), NM_001135099 (Hs), NM_015775 (Mm), NM_130424 (Rn)
RefSeq Protein NP_001128571 (Hs), NP_005647 (Hs), NP_056590 (Mm), NP_569108 (Rn)
UniProtKB O15393 (Hs), Q9JIQ8 (Mm)
Wikipedia TMPRSS2 (Hs)
Enzyme Reaction Click here for help
EC Number: 3.4.21.-

Download all structure-activity data for this target as a CSV file go icon to follow link

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
I-432 Small molecule or natural product Click here for species-specific activity table Hs Inhibition 9.1 pKi 7
⤷ pKi 9.1 (Ki 9x10-10 M) [7]
compound 5 [PMID: 21741839] Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 7.7 pKi 9
⤷ pKi 7.7 (Ki 2x10-8 M) [9]
MM3122 Small molecule or natural product Hs Inhibition 9.4 pIC50 6
⤷ pIC50 9.4 (IC50 4.3x10-10 M) [6]
Description: Inhibition of full-length hTMPRSS2 protease activity in vitro
N-0385 Peptide Click here for species-specific activity table Hs Inhibition 8.7 pIC50 8
⤷ pIC50 8.7 (IC50 1.9x10-9 M) [8]
nafamostat Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 7.0 pIC50 10
⤷ pIC50 7.0 (IC50 1x10-7 M) [10]
Description: Inhibition of TMPRSS2-dependent MERS-S-mediated membrane fusion in an in vitro reporter assay.
otamixaban Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Hs Inhibition 6.2 pIC50 4
⤷ pIC50 6.2 (IC50 6.2x10-7 M) [4]
Description: Determined in afluorogenic biochemical enzyme activity assay
camostat Small molecule or natural product Approved drug Click here for species-specific activity table Hs Inhibition 6.0 pIC50 10
⤷ pIC50 6.0 (IC50 1x10-6 M) [10]
Description: Inhibition of TMPRSS2-dependent MERS-S-mediated membrane fusion in an in vitro reporter assay.
Immuno Process Associations
Immuno Process:  Barrier integrity
GO Annotations:  Associated to 1 GO processes
GO:0046598 positive regulation of viral entry into host cell IDA
Immuno Process:  Antigen presentation
GO Annotations:  Associated to 1 GO processes, IEA only
click arrow to show/hide IEA associations
GO:0005044 scavenger receptor activity IEA
Biologically Significant Variants Click here for help
Type:  Non-synonymous variant
Species:  Human
Description:  This variant may be associated with reduced risk of developing severe COVID-19. It impacts the catalytic activity of TMPRSS2 in vitro, thereby reducing its supportive role in the SARS-CoV-2 spike-mediated infection process.
Amino acid change:  Val197Met
Nucleotide change:  589G>A
SNP accession:  rs12329760
References:  2
General Comments
TMPRSS2 is expressed on the epithelial cells of human lungs, and it is involved in the activation of viral glycoproteins/viral entry across a range of viruses, including influenza A virus, metapneumovirus, and some coronaviruses (e.g. SARS-CoV [1]). Emerging data suggest that the novel coronavirus SARS-CoV-2 (formerly referred to as 2019-nCoV) uses the same entry receptor (ACE2) that is used by SARS-CoV. Like SARS-CoV, SARS-CoV-2 exploits host TMPRSS2 for spike protein priming [3]. In this study in vitro SARS-CoV-2 entry was partially blocked by the protease inhibitor camostat (which has inhibitory action against TMPRSS2 [5]). Compounds that inhibit TMPRSS2 more potently than camostat are in development [8].

References

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1. Bertram S, Glowacka I, Müller MA, Lavender H, Gnirss K, Nehlmeier I, Niemeyer D, He Y, Simmons G, Drosten C et al.. (2011) Cleavage and activation of the severe acute respiratory syndrome coronavirus spike protein by human airway trypsin-like protease. J Virol, 85 (24): 13363-72. [PMID:21994442]

2. David A, Parkinson N, Peacock TP, Pairo-Castineira E, Khanna T, Cobat A, Tenesa A, Sancho-Shimizu V, GenOMICC Investigators, ISARIC4C Investigator et al.. (2021) A common TMPRSS2 variant protects against severe COVID-19. medRxiv, Preprint. DOI: 10.1101/2021.03.04.21252931

3. Hoffmann M, Kleine-Weber H, Schroeder S, Krüger N, Herrler T, Erichsen S, Schiergens TS, Herrler G, Wu NH, Nitsche A et al.. (2020) SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell, 181 (2): 271-280.e8. [PMID:32142651]

4. Hu X, Shrimp JH, Guo H, Xu M, Chen CZ, Zhu W, Zakharov AV, Jain S, Shinn P, Simeonov A et al.. (2021) Discovery of TMPRSS2 Inhibitors from Virtual Screening as a Potential Treatment of COVID-19. ACS Pharmacol Transl Sci, 4 (3): 1124-1135. [PMID:34136758]

5. Kawase M, Shirato K, van der Hoek L, Taguchi F, Matsuyama S. (2012) Simultaneous treatment of human bronchial epithelial cells with serine and cysteine protease inhibitors prevents severe acute respiratory syndrome coronavirus entry. J Virol, 86 (12): 6537-45. [PMID:22496216]

6. Mahoney M, Damalanka VC, Tartell MA, Chung DH, Lourenco AL, Pwee D, Mayer Bridwell AE, Hoffmann M, Voss J, Karmakar Pet al.. (2021) A novel class of TMPRSS2 inhibitors potently block SARS-CoV-2 and MERS-CoV viral entry and protect human epithelial lung cells. bioRxiv, Preprint. DOI: 10.1101/2021.05.06.442935

7. Pászti-Gere E, Czimmermann E, Ujhelyi G, Balla P, Maiwald A, Steinmetzer T. (2016) In vitro characterization of TMPRSS2 inhibition in IPEC-J2 cells. J Enzyme Inhib Med Chem, 31 (sup2): 123-129. [PMID:27277342]

8. Shapira T, Monreal IA, Dion SP, Buchholz DW, Imbiakha B, Olmstead AD, Jager M, Désilets A, Gao G, Martins M et al.. (2022) A TMPRSS2 inhibitor acts as a pan-SARS-CoV-2 prophylactic and therapeutic. Nature, [Epub ahead of print]. DOI: 10.1038/s41586-022-04661-w [PMID:35344983]

9. Sielaff F, Böttcher-Friebertshäuser E, Meyer D, Saupe SM, Volk IM, Garten W, Steinmetzer T. (2011) Development of substrate analogue inhibitors for the human airway trypsin-like protease HAT. Bioorg Med Chem Lett, 21 (16): 4860-4. [PMID:21741839]

10. Yamamoto M, Matsuyama S, Li X, Takeda M, Kawaguchi Y, Inoue JI, Matsuda Z. (2016) Identification of Nafamostat as a Potent Inhibitor of Middle East Respiratory Syndrome Coronavirus S Protein-Mediated Membrane Fusion Using the Split-Protein-Based Cell-Cell Fusion Assay. Antimicrob Agents Chemother, 60 (11): 6532-6539. [PMID:27550352]

How to cite this page

S1: Chymotrypsin: transmembrane serine protease 2. Last modified on 29/03/2022. Accessed on 02/04/2023. IUPHAR/BPS Guide to PHARMACOLOGY, https://www.guidetopharmacology.org/GRAC/ObjectDisplayForward?objectId=2421.