TLR8 | Toll-like receptor family | IUPHAR Guide to IMMUNOPHARMACOLOGY

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TLR8

  Target has curated data in GtoImmuPdb

Target id: 1758

Nomenclature: TLR8

Family: Toll-like receptor family

Annotation status:  image of a grey circle Awaiting annotation/under development. Please contact us if you can help with annotation.  » Email us

Gene and Protein Information
Species TM AA Chromosomal Location Gene Symbol Gene Name Reference
Human - 1015 Xp22 TLR8 toll like receptor 8
Mouse - 1009 X 78.29 cM Tlr8 toll-like receptor 8
Rat - - X Tlr8 toll-like receptor 8
Previous and Unofficial Names
toll-like receptor 8 | CD288 | UNQ249/PRO286
Database Links
CATH/Gene3D
ChEMBL Target
Ensembl Gene
Entrez Gene
Human Protein Atlas
KEGG Gene
OMIM
Pharos
UniProtKB
Wikipedia

Download all structure-activity data for this target as a CSV file

Inhibitors
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
CU-CPT8m Hs Inhibition 6.7 pKd 8
pKd 6.7 (Kd 2.2x10-7 M) [8]
Description: Dissociation constant measured using isothermal titration calorimetry (ITC) and the hTRL8 ectodomain.
CU-CPT8m Hs Inhibition 7.2 pIC50 8
pIC50 7.2 (IC50 6.7x10-8 M) [8]
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
motolimod Hs Agonist ~7.0 pEC50 4
pEC50 ~7.0 (EC50 ~1x10-7 M) [4]
selgantolimod Hs Agonist 6.7 pEC50 5
pEC50 6.7 (EC50 2.2x10-7 M) [5]
3M-002 Hs Agonist 5.9 pEC50 6
pEC50 5.9 (EC50 1.32x10-6 M) [6]
Description: Assessed as ability to activate NF-κB in HEK293 cells expressing human TLR8.
compound 12p [Larson et al., 2017] Hs Agonist 5.3 pEC50 2
pEC50 5.3 (EC50 4.98x10-6 M) [2]
Immunopharmacology Comments
TLR8 is an endosomal receptor detecting ssRNA [7]. It may also bind synthetic imidazoquinoline anti-viral drugs. TLR8 signalling is reported to reprogramme the glycolytic metabolic profile of Treg cells, in a mechanism that blocks Treg-induced immunosuppression in the local microenvironment and that can re-activate effective Treg anti-tumour activity [3]. Additional evidence that demonstrates the potential role of TLR8 in immuno-oncology is reviewed in [1]
Immuno Process Associations
Immuno Process:  Inflammation
GO Annotations:  Associated to 8 GO processes
GO:0002224 toll-like receptor signaling pathway IBA
GO:0008329 signaling pattern recognition receptor activity IBA
GO:0034158 toll-like receptor 8 signaling pathway IDA
GO:0034162 toll-like receptor 9 signaling pathway TAS
GO:0045087 innate immune response NAS
GO:0045089 positive regulation of innate immune response IDA
click arrow to show/hide IEA associations
GO:0001774 microglial cell activation IEA
GO:0002755 MyD88-dependent toll-like receptor signaling pathway IEA
Immuno Process:  T cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0016064 immunoglobulin mediated immune response TAS
Immuno Process:  B cell (activation)
GO Annotations:  Associated to 1 GO processes
GO:0016064 immunoglobulin mediated immune response TAS
Immuno Process:  Immune regulation
GO Annotations:  Associated to 6 GO processes
GO:0002224 toll-like receptor signaling pathway IBA
GO:0008329 signaling pattern recognition receptor activity IBA
GO:0034158 toll-like receptor 8 signaling pathway IDA
GO:0034162 toll-like receptor 9 signaling pathway TAS
GO:0045089 positive regulation of innate immune response IDA
click arrow to show/hide IEA associations
GO:0002755 MyD88-dependent toll-like receptor signaling pathway IEA
Immuno Process:  Cytokine production & signalling
GO Annotations:  Associated to 8 GO processes
GO:0032755 positive regulation of interleukin-6 production IBA
GO:0045078 positive regulation of interferon-gamma biosynthetic process IDA
GO:0045356 positive regulation of interferon-alpha biosynthetic process IDA
GO:0045359 positive regulation of interferon-beta biosynthetic process IDA
GO:0045416 positive regulation of interleukin-8 biosynthetic process IMP
GO:0050718 positive regulation of interleukin-1 beta secretion IDA
GO:2000778 positive regulation of interleukin-6 secretion IDA
GO:2001183 negative regulation of interleukin-12 secretion IDA
Immuno Process:  Cellular signalling
GO Annotations:  Associated to 6 GO processes
GO:0002224 toll-like receptor signaling pathway IBA
GO:0008329 signaling pattern recognition receptor activity IBA
GO:0034158 toll-like receptor 8 signaling pathway IDA
GO:0034162 toll-like receptor 9 signaling pathway TAS
click arrow to show/hide IEA associations
GO:0001774 microglial cell activation IEA
GO:0002755 MyD88-dependent toll-like receptor signaling pathway IEA
Clinically-Relevant Mutations and Pathophysiology
Disease:  Atherosclerosis susceptibility
Disease Ontology: DOID:1936
OMIM: 108725
Disease:  Crimean-Congo hemorrhagic fever
Disease Ontology: DOID:12287
Disease:  Fibrosis
Disease:  Mycobacterium tuberculosis, susceptibility to
Disease Ontology: DOID:399
OMIM: 607948

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. 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]

3. Li L, Liu X, Sanders KL, Edwards JL, Ye J, Si F, Gao A, Huang L, Hsueh EC, Ford DA et al.. (2019) TLR8-Mediated Metabolic Control of Human Treg Function: A Mechanistic Target for Cancer Immunotherapy. Cell Metab., 29 (1): 103-123.e5. DOI: https://doi.org/10.1016/j.cmet.2018.09.020 [PMID:30344014]

4. Lu H, Dietsch GN, Matthews MA, Yang Y, Ghanekar S, Inokuma M, Suni M, Maino VC, Henderson KE, Howbert JJ et al.. (2012) VTX-2337 is a novel TLR8 agonist that activates NK cells and augments ADCC. Clin. Cancer Res., 18 (2): 499-509. [PMID:22128302]

5. Mackman RL, Mish M, Chin G, Perry JK, Appleby T, Aktoudianakis V, Metobo S, Pyun P, Niu C, Daffis S et al.. (2020) Discovery of GS-9688 (Selgantolimod) as a Potent and Selective Oral Toll-Like Receptor 8 Agonist for the Treatment of Chronic Hepatitis B. J. Med. Chem., [Epub ahead of print]. [PMID:32407112]

6. Salunke DB, Yoo E, Shukla NM, Balakrishna R, Malladi SS, Serafin KJ, Day VW, Wang X, David SA. (2012) Structure-activity relationships in human Toll-like receptor 8-active 2,3-diamino-furo[2,3-c]pyridines. J. Med. Chem., 55 (18): 8137-51. [PMID:22924757]

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

8. Zhang S, Hu Z, Tanji H, Jiang S, Das N, Li J, Sakaniwa K, Jin J, Bian Y, Ohto U et al.. (2018) Small-molecule inhibition of TLR8 through stabilization of its resting state. Nat. Chem. Biol., 14 (1): 58-64. [PMID:29155428]

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