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TLR7

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1757

Nomenclature: TLR7

Family: Toll-like receptor family

Contents:

Gene and Protein Information Click here for help
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human 1 1049 Xp22.2 TLR7 toll like receptor 7
Mouse 1 1050 X F5 Tlr7 toll-like receptor 7
Rat - - Xq21 Tlr7 toll-like receptor 7
Previous and Unofficial Names Click here for help
toll-like receptor 7 | UNQ248/PRO285-like
Database Links Click here for help
Alphafold Q9NYK1 (Hs), P58681 (Mm)
CATH/Gene3D 3.40.50.10140, 3.80.10.10
ChEMBL Target CHEMBL5936 (Hs), CHEMBL6085 (Mm)
DrugBank Target Q9NYK1 (Hs)
Ensembl Gene ENSG00000196664 (Hs), ENSMUSG00000044583 (Mm), ENSRNOG00000004249 (Rn)
Entrez Gene 51284 (Hs), 170743 (Mm), 317468 (Rn)
Human Protein Atlas ENSG00000196664 (Hs)
KEGG Gene hsa:51284 (Hs), mmu:170743 (Mm), rno:317468 (Rn)
OMIM 300365 (Hs)
Pharos Q9NYK1 (Hs)
UniProtKB Q9NYK1 (Hs), P58681 (Mm)
Wikipedia TLR7 (Hs)

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

Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
resiquimod Small molecule or natural product Click here for species-specific activity table Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 5.9 pEC50 7,9,11
⤷ pEC50 5.9 (EC50 1.34x10-6 M) [7,9,11]
852A Small molecule or natural product Immunopharmacology Ligand Hs Agonist 5.6 pEC50 13
⤷ pEC50 5.6 (EC50 2.657x10-6 M) [13]
852A Small molecule or natural product Immunopharmacology Ligand Mm Agonist 5.2 pEC50 13
⤷ pEC50 5.2 (EC50 6.224x10-6 M) [13]
imiquimod Small molecule or natural product Approved drug Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 4.9 pEC50 11
⤷ pEC50 4.9 (EC50 1.14x10-5 M) [11]
compound 27 [WO2019226977A1] Small molecule or natural product Hs Agonist 3.4 pEC50 20
⤷ pEC50 3.4 (EC50 3.76x10-4 M) [20]
Description: EC50 determined in a TLR7 reporter gene assay in HEK293 cells
loxoribine Small molecule or natural product Ligand has a PDB structure Hs Agonist - - 6
⤷ [6]
GSK2245035 Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Agonist - - 2
⤷ [2]
View species-specific agonist tables
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
enpatoran Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Antagonist >6.0 pIC50 15
⤷ pIC50 >6.0 (IC50 <1x10-6 M) [15]
Description: Inhibition of activation of a TLR7/NFkB reporter in HEK293 cells (binned value).
hydroxychloroquine Small molecule or natural product Approved drug Primary target of this compound Click here for species-specific activity table Immunopharmacology Ligand Guide to Malaria Pharmacology Ligand Hs Antagonist 5.6 pIC50 10
⤷ pIC50 5.6 (IC50 2.78x10-6 M) [10]
Description: Inhibition of hTLR7 R848-induced luciferase reporter gene activation.
compound 10a [PMID: 31283223] Small molecule or natural product Immunopharmacology Ligand Hs Antagonist 5.1 pIC50 3
⤷ pIC50 5.1 (IC50 8.2x10-6 M) [3]
Immunopharmacology Comments
TLR7 is an endosomal receptor detecting ssRNA [18]. It may also bind synthetic imidazoquinoline anti-viral drugs. The potential role of TLR7 in immuno-oncology is reviewed in [1].
TLR7 lies on the X chormosome, and genetic variants are associated with sex-biased differences in the immune response to viral infections, vis type I IFN production [5,12,14,19]. Elevated TLR7 expression and subsequent increased TLR7-induced type I IFN responses may also underlie the female-bias in development of autoimmune diseases [8,12,17].
Clinically-Relevant Mutations and Pathophysiology Click here for help
Disease:  Hepatitis C infection
Disease Ontology: DOID:1883
Disease:  Human immunodeficiency virus type 1, susceptibility to
Synonyms: Human immunodeficiency virus infectious disease [Disease Ontology: DOID:526]
Disease Ontology: DOID:526
OMIM: 609423
Orphanet: ORPHA319269
Disease:  Systemic lupus erythematosus
Description: SLE is a complex autoimmune disease that is characterised by inflammation of various connective tissues, and symptoms include dermatitis, arthritis, inflammation of the kidneys (glomerulonephritis), vasculitis, inflammation of the tissue surrounding the heart, and seizures. It is caused by the production of autoantibodies against widely expressed nuclear, cytoplasmic, and cell surface molecules. Extracellular RNA in the circulation in combination with the presence of autoantibodies potently stimulates interferon production and immune system activation.
Disease Ontology: DOID:9074
OMIM: 152700
Orphanet: ORPHA536
Clinically-Relevant Mutations and Pathophysiology Comments
Predicted loss-of-function genetic variants in TLR7 have been identified in young (aged 21-32), otherwise healthy sons, from two unrelated families, who suffered from severe COVID-19 [19]. In one family two sons had inherited aTLR7 truncating mutation (c.2129_2132del; p.[Gln710Argfs*18]) from their heterozygous mother. In the other family two sons carried a missense mutation that was predicted as deleterious (c.2383G>T; p.[Val795Phe]). Compared to primary immune cells from their parents and controls, PBMCs from the affected males failed to produce IFNγ in response to TLR7 agonism with imiquimod. Although rare, this report suggests that TLR7-mediated immunodeficiency may predispose to severe infections caused by severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). In addition, because TLR7 escapes X inactivation [16-17], it may be possible that TLR7 gene dosage could in part explain the difference in distribution of severe COVID-19 cases between the sexes, as it appears to in other viral infections [5,12,14].
Biologically Significant Variants Click here for help
Type:  Missense mutation
Species:  Human
Description:  A gain-of-function mutation that enhances TLR7 signalling in response to detection of guanosine, was identified in a child with severe systemic lupus erythematosus. In a mouse model the mutation alone was sufficient to induce lupus.
Amino acid change:  Y264H
References:  4

References

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1. Adams JL, Smothers J, Srinivasan R, Hoos A. (2015) Big opportunities for small molecules in immuno-oncology. Nat Rev Drug Discov, 14 (9): 603-22. [PMID:26228631]

2. Biggadike K, Ahmed M, Ball DI, Coe DM, Dalmas Wilk DA, Edwards CD, Gibbon BH, Hardy CJ, Hermitage SA, Hessey JO et al.. (2016) Discovery of 6-Amino-2-{[(1S)-1-methylbutyl]oxy}-9-[5-(1-piperidinyl)pentyl]-7,9-dihydro-8H-purin-8-one (GSK2245035), a Highly Potent and Selective Intranasal Toll-Like Receptor 7 Agonist for the Treatment of Asthma. J Med Chem, 59 (5): 1711-26. [PMID:26861551]

3. Bou Karroum N, Moarbess G, Guichou JF, Bonnet PA, Patinote C, Bouharoun-Tayoun H, Chamat S, Cuq P, Diab-Assaf M, Kassab I et al.. (2019) Novel and Selective TLR7 Antagonists among the Imidazo[1,2-a]pyrazines, Imidazo[1,5-a]quinoxalines, and Pyrazolo[1,5-a]quinoxalines Series. J Med Chem, 62 (15): 7015-7031. [PMID:31283223]

4. Brown GJ, Cañete PF, Wang H, Medhavy A, Bones J, Roco JA, He Y, Qin Y, Cappello J, Ellyard JI et al.. (2022) TLR7 gain-of-function genetic variation causes human lupus. Nature, 605 (7909): 349-356. [PMID:35477763]

5. Buschow SI, Biesta PJ, Groothuismink ZMA, Erler NS, Vanwolleghem T, Ho E, Najera I, Ait-Goughoulte M, de Knegt RJ, Boonstra A et al.. (2018) TLR7 polymorphism, sex and chronic HBV infection influence plasmacytoid DC maturation by TLR7 ligands. Antiviral Res, 157: 27-37. [PMID:29964062]

6. Heil F, Ahmad-Nejad P, Hemmi H, Hochrein H, Ampenberger F, Gellert T, Dietrich H, Lipford G, Takeda K, Akira S et al.. (2003) The Toll-like receptor 7 (TLR7)-specific stimulus loxoribine uncovers a strong relationship within the TLR7, 8 and 9 subfamily. Eur J Immunol, 33 (11): 2987-97. [PMID:14579267]

7. Hemmi H, Kaisho T, Takeuchi O, Sato S, Sanjo H, Hoshino K, Horiuchi T, Tomizawa H, Takeda K, Akira S. (2002) Small anti-viral compounds activate immune cells via the TLR7 MyD88-dependent signaling pathway. Nat Immunol, 3 (2): 196-200. [PMID:11812998]

8. Henmyr V, Carlberg D, Manderstedt E, Lind-Halldén C, Säll T, Cardell LO, Halldén C. (2017) Genetic variation of the Toll-like receptors in a Swedish allergic rhinitis case population. BMC Med Genet, 18 (1): 18. [PMID:28228119]

9. Jurk M, Heil F, Vollmer J, Schetter C, Krieg AM, Wagner H, Lipford G, Bauer S. (2002) Human TLR7 or TLR8 independently confer responsiveness to the antiviral compound R-848. Nat Immunol, 3 (6): 499. [PMID:12032557]

10. Lamphier M, Zheng W, Latz E, Spyvee M, Hansen H, Rose J, Genest M, Yang H, Shaffer C, Zhao Y et al.. (2014) Novel small molecule inhibitors of TLR7 and TLR9: mechanism of action and efficacy in vivo. Mol Pharmacol, 85 (3): 429-40. [PMID:24342772]

11. Larson P, Kucaba TA, Xiong Z, Olin M, Griffith TS, Ferguson DM. (2017) Design and Synthesis of N1-Modified Imidazoquinoline Agonists for Selective Activation of Toll-like Receptors 7 and 8. ACS Med Chem Lett, 8 (11): 1148-1152. [PMID:29152046]

12. Meier A, Chang JJ, Chan ES, Pollard RB, Sidhu HK, Kulkarni S, Wen TF, Lindsay RJ, Orellana L, Mildvan D et al.. (2009) Sex differences in the Toll-like receptor-mediated response of plasmacytoid dendritic cells to HIV-1. Nat Med, 15 (8): 955-9. [PMID:19597505]

13. Nakamura T, Wada H, Kurebayashi H, McInally T, Bonnert R, Isobe Y. (2013) Synthesis and evaluation of 8-oxoadenine derivatives as potent Toll-like receptor 7 agonists with high water solubility. Bioorg Med Chem Lett, 23 (3): 669-72. [PMID:23265901]

14. Oh DY, Baumann K, Hamouda O, Eckert JK, Neumann K, Kücherer C, Bartmeyer B, Poggensee G, Oh N, Pruss A et al.. (2009) A frequent functional toll-like receptor 7 polymorphism is associated with accelerated HIV-1 disease progression. AIDS, 23 (3): 297-307. [PMID:19114863]

15. Sherer BA, Brugger N. (2017) Polycyclic tlr7/8 antagonists and use thereof in the treatment of immune disorders. Patent number: WO2017106607A1. Assignee: Merck Patent Gmbh. Priority date: 17/12/2015. Publication date: 22/06/2017.

16. Souyris M, Cenac C, Azar P, Daviaud D, Canivet A, Grunenwald S, Pienkowski C, Chaumeil J, Mejía JE, Guéry JC. (2018) TLR7 escapes X chromosome inactivation in immune cells. Sci Immunol, 3 (19). DOI: 10.1126/sciimmunol.aap8855 [PMID:29374079]

17. Souyris M, Mejía JE, Chaumeil J, Guéry JC. (2019) Female predisposition to TLR7-driven autoimmunity: gene dosage and the escape from X chromosome inactivation. Semin Immunopathol, 41 (2): 153-164. [PMID:30276444]

18. Uematsu S, Akira S. (2008) Toll-Like receptors (TLRs) and their ligands. Handb Exp Pharmacol, (183): 1-20. [PMID:18071652]

19. van der Made CI, Simons A, Schuurs-Hoeijmakers J, van den Heuvel G, Mantere T, Kersten S, van Deuren RC, Steehouwer M, van Reijmersdal SV, Jaeger M et al.. (2020) Presence of Genetic Variants Among Young Men With Severe COVID-19. JAMA, 324 (7): 663-673. [PMID:32706371]

20. Webber SE, Appleman JR. (2019) Tlr7 agonists. Patent number: WO2019226977A1. Assignee: Primmune Therapeutics, Inc.. Priority date: 25/05/2018. Publication date: 28/11/2019.

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