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TLR8

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Immunopharmacology Ligand  Target has curated data in GtoImmuPdb

Target id: 1758

Nomenclature: TLR8

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 1041 Xp22.2 TLR8 toll like receptor 8
Mouse 1 1032 X F5 Tlr8 toll-like receptor 8
Rat - - X Tlr8 toll-like receptor 8
Previous and Unofficial Names Click here for help
toll-like receptor 8 | CD288 | UNQ249/PRO286
Database Links Click here for help
Alphafold Q9NR97 (Hs), P58682 (Mm)
CATH/Gene3D 3.40.50.10140, 3.80.10.10
ChEMBL Target CHEMBL5805 (Hs), CHEMBL2146339 (Mm)
Ensembl Gene ENSG00000101916 (Hs), ENSMUSG00000040522 (Mm), ENSRNOG00000045992 (Rn)
Entrez Gene 51311 (Hs), 170744 (Mm)
Human Protein Atlas ENSG00000101916 (Hs)
KEGG Gene hsa:51311 (Hs), mmu:170744 (Mm)
OMIM 300366 (Hs)
Pharos Q9NR97 (Hs)
UniProtKB Q9NR97 (Hs), P58682 (Mm)
Wikipedia TLR8 (Hs)
Selected 3D Structures Click here for help
Image of receptor 3D structure from RCSB PDB
Description:  Human TLR8 bound to the potent agonist, GS-9688 (selgantolimod)
PDB Id:  6WML
Ligand:  selgantolimod
Resolution:  2.5Å
Species:  Human
References:  6

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
CU-CPT8m Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 6.7 pKd 9
⤷ pKd 6.7 (Kd 2.2x10-7 M) [9]
Description: Dissociation constant measured using isothermal titration calorimetry (ITC) and the hTRL8 ectodomain.
CU-CPT8m Small molecule or natural product Ligand has a PDB structure Immunopharmacology Ligand Hs Inhibition 7.2 pIC50 9
⤷ pIC50 7.2 (IC50 6.7x10-8 M) [9]
Agonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
motolimod Small molecule or natural product Immunopharmacology Ligand Hs Agonist ~7.0 pEC50 5
⤷ pEC50 ~7.0 (EC50 ~1x10-7 M) [5]
selgantolimod Small molecule or natural product Ligand has a PDB structure Hs Agonist 6.7 pEC50 6
⤷ pEC50 6.7 (EC50 2.2x10-7 M) [6]
3M-002 Small molecule or natural product Primary target of this compound Ligand has a PDB structure Immunopharmacology Ligand Hs Agonist 5.9 pEC50 7
⤷ pEC50 5.9 (EC50 1.32x10-6 M) [7]
Description: Assessed as ability to activate NF-κB in HEK293 cells expressing human TLR8.
compound 12p [Larson et al., 2017] Small molecule or natural product Primary target of this compound Immunopharmacology Ligand Hs Agonist 5.3 pEC50 3
⤷ pEC50 5.3 (EC50 4.98x10-6 M) [3]
Antagonists
Key to terms and symbols View all chemical structures Click column headers to sort
Ligand Sp. Action Value Parameter Reference
compound 15 [PMID: 35450354] Small molecule or natural product Hs Antagonist 8.7 pIC50 2
⤷ pIC50 8.7 (IC50 2x10-9 M) [2]
Description: Binding determined in a FRET assay
Immunopharmacology Comments
TLR8 is an endosomal receptor detecting ssRNA [8]. 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 [4]. Additional evidence that demonstrates the potential role of TLR8 in immuno-oncology is reviewed in [1]
Immuno Process Associations
Immuno Process:  Inflammation
Immuno Process:  T cell (activation)
Immuno Process:  B cell (activation)
Immuno Process:  Immune regulation
Immuno Process:  Cytokine production & signalling
Immuno Process:  Cellular signalling
Clinically-Relevant Mutations and Pathophysiology Click here for help
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. Betschart C, Faller M, Zink F, Hemmig R, Blank J, Vangrevelinghe E, Bourrel M, Glatthar R, Behnke D, Barker K et al.. (2022) Structure-Based Optimization of a Fragment-like TLR8 Binding Screening Hit to an In Vivo Efficacious TLR7/8 Antagonist. ACS Med Chem Lett, 13 (4): 658-664. [PMID:35450354]

3. 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]

4. 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]

5. 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]

6. 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, 63 (18): 10188-10203. [PMID:32407112]

7. 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]

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

9. 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]

Contributors

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