Target Information
| Target General Information | Top | |||||
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| Target ID |
T48703
(Former ID: TTDC00056)
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| Target Name |
Toll-like receptor 8 (TLR8)
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| Synonyms |
UNQ249/PRO286; CD288 antigen; CD288
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| Gene Name |
TLR8
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| Target Type |
Clinical trial target
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[1] | ||||
| Disease | [+] 9 Target-related Diseases | + | ||||
| 1 | Epidermal dysplasias [ICD-11: EK90] | |||||
| 2 | Hepatitis virus infection [ICD-11: 1E50-1E51] | |||||
| 3 | Mycosis fungoides [ICD-11: 2B01] | |||||
| 4 | Herpes simplex infection [ICD-11: 1F00] | |||||
| 5 | Lupus erythematosus [ICD-11: 4A40] | |||||
| 6 | Melanoma [ICD-11: 2C30] | |||||
| 7 | Solid tumour/cancer [ICD-11: 2A00-2F9Z] | |||||
| 8 | Squamous cell carcinoma [ICD-11: 2B60-2D01] | |||||
| 9 | Vasomotor/allergic rhinitis [ICD-11: CA08] | |||||
| Function |
Key component of innate and adaptive immunity. TLRs (Toll-like receptors) control host immune response against pathogens through recognition of molecular patterns specific to microorganisms. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response.
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| BioChemical Class |
Toll-like receptor
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| UniProt ID | ||||||
| Sequence |
MENMFLQSSMLTCIFLLISGSCELCAEENFSRSYPCDEKKQNDSVIAECSNRRLQEVPQT
VGKYVTELDLSDNFITHITNESFQGLQNLTKINLNHNPNVQHQNGNPGIQSNGLNITDGA FLNLKNLRELLLEDNQLPQIPSGLPESLTELSLIQNNIYNITKEGISRLINLKNLYLAWN CYFNKVCEKTNIEDGVFETLTNLELLSLSFNSLSHVPPKLPSSLRKLFLSNTQIKYISEE DFKGLINLTLLDLSGNCPRCFNAPFPCVPCDGGASINIDRFAFQNLTQLRYLNLSSTSLR KINAAWFKNMPHLKVLDLEFNYLVGEIASGAFLTMLPRLEILDLSFNYIKGSYPQHINIS RNFSKLLSLRALHLRGYVFQELREDDFQPLMQLPNLSTINLGINFIKQIDFKLFQNFSNL EIIYLSENRISPLVKDTRQSYANSSSFQRHIRKRRSTDFEFDPHSNFYHFTRPLIKPQCA AYGKALDLSLNSIFFIGPNQFENLPDIACLNLSANSNAQVLSGTEFSAIPHVKYLDLTNN RLDFDNASALTELSDLEVLDLSYNSHYFRIAGVTHHLEFIQNFTNLKVLNLSHNNIYTLT DKYNLESKSLVELVFSGNRLDILWNDDDNRYISIFKGLKNLTRLDLSLNRLKHIPNEAFL NLPASLTELHINDNMLKFFNWTLLQQFPRLELLDLRGNKLLFLTDSLSDFTSSLRTLLLS HNRISHLPSGFLSEVSSLKHLDLSSNLLKTINKSALETKTTTKLSMLELHGNPFECTCDI GDFRRWMDEHLNVKIPRLVDVICASPGDQRGKSIVSLELTTCVSDVTAVILFFFTFFITT MVMLAALAHHLFYWDVWFIYNVCLAKVKGYRSLSTSQTFYDAYISYDTKDASVTDWVINE LRYHLEESRDKNVLLCLEERDWDPGLAIIDNLMQSINQSKKTVFVLTKKYAKSWNFKTAF YLALQRLMDENMDVIIFILLEPVLQHSQYLRLRQRICKSSILQWPDNPKAEGLFWQTLRN VVLTENDSRYNNMYVDSIKQY Click to Show/Hide
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| 3D Structure | Click to Show 3D Structure of This Target | AlphaFold | ||||
| HIT2.0 ID | T05V67 | |||||
| Drugs and Modes of Action | Top | |||||
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| Clinical Trial Drug(s) | [+] 11 Clinical Trial Drugs | + | ||||
| 1 | Afimetoran | Drug Info | Phase 2 | Systemic lupus erythematosus | [2] | |
| 2 | Resiquimod | Drug Info | Phase 2 | Actinic keratosis | [3] | |
| 3 | Selgantolimod | Drug Info | Phase 2 | Hepatitis B | [4] | |
| 4 | NKTR-262 | Drug Info | Phase 1/2 | Solid tumour/cancer | [5] | |
| 5 | CPG 52364 | Drug Info | Phase 1 | Systemic lupus erythematosus | [6] | |
| 6 | CV8102 | Drug Info | Phase 1 | Melanoma | [7] | |
| 7 | DN1508052 | Drug Info | Phase 1 | Solid tumour/cancer | [8] | |
| 8 | GSK5251738 | Drug Info | Phase 1 | Hepatitis B | [9] | |
| 9 | MEDI9197 | Drug Info | Phase 1 | Solid tumour/cancer | [10] | |
| 10 | SBT6050 | Drug Info | Phase 1 | Solid tumour/cancer | [11] | |
| 11 | VTX-1463 | Drug Info | Phase 1 | Allergic rhinitis | [12] | |
| Discontinued Drug(s) | [+] 2 Discontinued Drugs | + | ||||
| 1 | VTX-2337 | Drug Info | Discontinued in Phase 2 | Allergy | [13] | |
| 2 | IM0-8400 | Drug Info | Discontinued in Phase 1/2 | Diffuse large B-cell lymphoma | [14] | |
| Mode of Action | [+] 4 Modes of Action | + | ||||
| Inhibitor | [+] 2 Inhibitor drugs | + | ||||
| 1 | Afimetoran | Drug Info | [15] | |||
| 2 | ODN-1411 | Drug Info | [25] | |||
| Modulator | [+] 3 Modulator drugs | + | ||||
| 1 | Resiquimod | Drug Info | [16] | |||
| 2 | VTX-2337 | Drug Info | [1] | |||
| 3 | VTX-744 | Drug Info | [26] | |||
| Agonist | [+] 8 Agonist drugs | + | ||||
| 1 | Selgantolimod | Drug Info | [17] | |||
| 2 | NKTR-262 | Drug Info | [18] | |||
| 3 | CV8102 | Drug Info | [20] | |||
| 4 | DN1508052 | Drug Info | [21] | |||
| 5 | GSK5251738 | Drug Info | [9] | |||
| 6 | MEDI9197 | Drug Info | [10] | |||
| 7 | SBT6050 | Drug Info | [22] | |||
| 8 | VTX-1463 | Drug Info | [23] | |||
| Antagonist | [+] 3 Antagonist drugs | + | ||||
| 1 | CPG 52364 | Drug Info | [19] | |||
| 2 | IM0-8400 | Drug Info | [24] | |||
| 3 | VTX-763 | Drug Info | [26] | |||
| Cell-based Target Expression Variations | Top | |||||
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| Cell-based Target Expression Variations | ||||||
| Drug Binding Sites of Target | Top | |||||
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| Ligand Name: Uridine | Ligand Info | |||||
| Structure Description | Crystal structure of human TLR8 in complex with uridine mononucleoside | PDB:4R0A | ||||
| Method | X-ray diffraction | Resolution | 1.90 Å | Mutation | No | [27] |
| PDB Sequence |
RSYPCDEKKQ
41 NDSVIAECSN51 RRLQEVPQTV61 GKYVTELDLS71 DNFITHITNE81 SFQGLQNLTK 91 INLNHNPNVG113 LNITDGAFLN123 LKNLRELLLE133 DNQLPQIPSG143 LPESLTELSL 153 IQNNIYNITK163 EGISRLINLK173 NLYLAWNCYF183 NKVCEKTNIE193 DGVFETLTNL 203 ELLSLSFNSL213 SHVPPKLPSS223 LRKLFLSNTQ233 IKYISEEDFK243 GLINLTLLDL 253 SGNCPRCFNA263 PFPCVPCDGG273 ASINIDRFAF283 QNLTQLRYLN293 LSSTSLRKIN 303 AAWFKNMPHL313 KVLDLEFNYL323 VGEIASGAFL333 TMLPRLEILD343 LSFNYIKGSY 353 PQHINISRNF363 SKLLSLRALH373 LRGYVFQELR383 EDDFQPLMQL393 PNLSTINLGI 403 NFIKQIDFKL413 FQNFSNLEII423 YLSENRISPL433 EFDPHSNFYH469 FTRPLIKPQC 479 AAYGKALDLS489 LNSIFFIGPN499 QFENLPDIAC509 LNLSANSNAQ519 VLSGTEFSAI 529 PHVKYLDLTN539 NRLDFDNASA549 LTELSDLEVL559 DLSYNSHYFR569 IAGVTHHLEF 579 IQNFTNLKVL589 NLSHNNIYTL599 TDKYNLESKS609 LVELVFSGNR619 LDILWNDDDN 629 RYISIFKGLK639 NLTRLDLSLN649 RLKHIPNEAF659 LNLPASLTEL669 HINDNMLKFF 679 NWTLLQQFPR689 LELLDLRGNK699 LLFLTDSLSD709 FTSSLRTLLL719 SHNRISHLPS 729 GFLSEVSSLK739 HLDLSSNLLK749 TINKSALETK759 TTTKLSMLEL769 HGNPFECTCD 779 IGDFRRWMDE789 HLNVKIPRLV799 DVICASPGDQ809 RGKSIVSL
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Ligand Name: Resiquimod | Ligand Info | |||||
| Structure Description | Crystal structure of human TLR8 in complex with Resiquimod (R848) crystal form 3 | PDB:3W3N | ||||
| Method | X-ray diffraction | Resolution | 2.10 Å | Mutation | No | [28] |
| PDB Sequence |
SRSYPCDEKK
40 QNDSVIAECS50 NRRLQEVPQT60 VGKYVTELDL70 SDNFITHITN80 ESFQGLQNLT 90 KINLNHNPNV100 GLNITDGAFL122 NLKNLRELLL132 EDNQLPQIPS142 GLPESLTELS 152 LIQNNIYNIT162 KEGISRLINL172 KNLYLAWNCY182 FNKVCEKTNI192 EDGVFETLTN 202 LELLSLSFNS212 LSHVPPKLPS222 SLRKLFLSNT232 QIKYISEEDF242 KGLINLTLLD 252 LSGNCPRCFN262 APFPCVPCDG272 GASINIDRFA282 FQNLTQLRYL292 NLSSTSLRKI 302 NAAWFKNMPH312 LKVLDLEFNY322 LVGEIASGAF332 LTMLPRLEIL342 DLSFNYIKGS 352 YPQHINISRN362 FSKLLSLRAL372 HLRGYVFQEL382 REDDFQPLMQ392 LPNLSTINLG 402 INFIKQIDFK412 LFQNFSNLEI422 IYLSENRISP432 LFEFDPHSNF467 YHFTRPLIKP 477 QCAAYGKALD487 LSLNSIFFIG497 PNQFENLPDI507 ACLNLSANSN517 AQVLSGTEFS 527 AIPHVKYLDL537 TNNRLDFDNA547 SALTELSDLE557 VLDLSYNSHY567 FRIAGVTHHL 577 EFIQNFTNLK587 VLNLSHNNIY597 TLTDKYNLES607 KSLVELVFSG617 NRLDILWNDD 627 DNRYISIFKG637 LKNLTRLDLS647 LNRLKHIPNE657 AFLNLPASLT667 ELHINDNMLK 677 FFNWTLLQQF687 PRLELLDLRG697 NKLLFLTDSL707 SDFTSSLRTL717 LLSHNRISHL 727 PSGFLSEVSS737 LKHLDLSSNL747 LKTINKSALE757 TKTTTKLSML767 ELHGNPFECT 777 CDIGDFRRWM787 DEHLNVKIPR797 LVDVICASPG807 DQRGKSIVSL817 E |
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| Click to View More Binding Site Information of This Target and Ligand Pair | ||||||
| Click to View More Binding Site Information of This Target with Different Ligands | ||||||
| Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Tissue Distribution
of target is determined from a proteomics study that quantified more than 12,000 genes across 32 normal human tissues. Tissue Specificity (TS) score was used to define the enrichment of target across tissues.
The distribution of targets among different tissues or organs need to be taken into consideration when assessing the target druggability, as it is generally accepted that the wider the target distribution, the greater the concern over potential adverse effects
(Nat Rev Drug Discov, 20: 64-81, 2021).
Human Pathway Affiliation
of target is determined by the life-essential pathways provided on KEGG database. The target-affiliated pathways were defined based on the following two criteria (a) the pathways of the studied target should be life-essential for both healthy individuals and patients, and (b) the studied target should occupy an upstream position in the pathways and therefore had the ability to regulate biological function.
Targets involved in a fewer pathways have greater likelihood to be successfully developed, while those associated with more human pathways increase the chance of undesirable interferences with other human processes
(Pharmacol Rev, 58: 259-279, 2006).
Biological Network Descriptors
of target is determined based on a human protein-protein interactions (PPI) network consisting of 9,309 proteins and 52,713 PPIs, which were with a high confidence score of ≥ 0.95 collected from STRING database.
The network properties of targets based on protein-protein interactions (PPIs) have been widely adopted for the assessment of target’s druggability. Proteins with high node degree tend to have a high impact on network function through multiple interactions, while proteins with high betweenness centrality are regarded to be central for communication in interaction networks and regulate the flow of signaling information
(Front Pharmacol, 9, 1245, 2018;
Curr Opin Struct Biol. 44:134-142, 2017).
Human Similarity Proteins
Human Tissue Distribution
Human Pathway Affiliation
Biological Network Descriptors
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Note:
If a protein has TS (tissue specficity) scores at least in one tissue >= 2.5, this protein is called tissue-enriched (including tissue-enriched-but-not-specific and tissue-specific). In the plots, the vertical lines are at thresholds 2.5 and 4.
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| KEGG Pathway | Pathway ID | Affiliated Target | Pathway Map |
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| Neutrophil extracellular trap formation | hsa04613 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Toll-like receptor signaling pathway | hsa04620 | Affiliated Target |
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| Class: Organismal Systems => Immune system | Pathway Hierarchy | ||
| Degree | 2 | Degree centrality | 2.15E-04 | Betweenness centrality | 4.39E-06 |
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| Closeness centrality | 1.92E-01 | Radiality | 1.33E+01 | Clustering coefficient | 0.00E+00 |
| Neighborhood connectivity | 2.50E+01 | Topological coefficient | 5.33E-01 | Eccentricity | 12 |
| Download | Click to Download the Full PPI Network of This Target | ||||
| Chemical Structure based Activity Landscape of Target | Top |
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| Drug Property Profile of Target | Top | |
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| (1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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| (3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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| (5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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| "RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five | ||
| Co-Targets | Top | |||||
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| Co-Targets | ||||||
| Target Poor or Non Binders | Top | |||||
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| Target Poor or Non Binders | ||||||
| Target Affiliated Biological Pathways | Top | |||||
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| KEGG Pathway | [+] 1 KEGG Pathways | + | ||||
| 1 | Toll-like receptor signaling pathway | |||||
| NetPath Pathway | [+] 2 NetPath Pathways | + | ||||
| 1 | Leptin Signaling Pathway | |||||
| 2 | TCR Signaling Pathway | |||||
| Panther Pathway | [+] 1 Panther Pathways | + | ||||
| 1 | Toll receptor signaling pathway | |||||
| Reactome | [+] 4 Reactome Pathways | + | ||||
| 1 | Trafficking and processing of endosomal TLR | |||||
| 2 | TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling | |||||
| 3 | TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation | |||||
| 4 | MyD88 dependent cascade initiated on endosome | |||||
| WikiPathways | [+] 5 WikiPathways | + | ||||
| 1 | Toll-like receptor signaling pathway | |||||
| 2 | Toll-Like Receptors Cascades | |||||
| 3 | MyD88 dependent cascade initiated on endosome | |||||
| 4 | Trafficking and processing of endosomal TLR | |||||
| 5 | Regulation of toll-like receptor signaling pathway | |||||
| Target-Related Models and Studies | Top | |||||
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| Target Validation | ||||||
| References | Top | |||||
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| REF 1 | Clinical pipeline report, company report or official report of Array BioPharma (Drug: Motolimod / VTX2337). | |||||
| REF 2 | ClinicalTrials.gov (NCT04895696) A Phase 2, Multicenter, Randomized, Double-blind, Placebo-Controlled, Study to Evaluate the Efficacy and Safety of Afimetoran in Participants With Active Systemic Lupus Erythematosus. U.S.National Institutes of Health. | |||||
| REF 3 | ClinicalTrials.gov (NCT01583816) Dose-finding, Safety, Efficacy Trial of Topical Resiquimod in Patients With Multiple Actinic Keratosis Lesions. U.S. National Institutes of Health. | |||||
| REF 4 | ClinicalTrials.gov (NCT03491553) Safety, Tolerability and Antiviral Activity of Selgantolimod in Virally-Suppressed Adults With Chronic Hepatitis B. U.S. National Institutes of Health. | |||||
| REF 5 | ClinicalTrials.gov (NCT03435640) A Study of NKTR-262 in Combination With Bempegaldesleukin (NKTR-214) and With Bempegaldesleukin Plus Nivolumab in Patients With Locally Advanced or Metastatic Solid Tumor Malignancies (REVEAL). U.S. National Institutes of Health. | |||||
| REF 6 | Treatment of systemic lupus erythematosus: new therapeutic avenues and blind alleys. Nat Rev Rheumatol. 2014 Jan;10(1):23-34. | |||||
| REF 7 | ClinicalTrials.gov (NCT03291002) Study of Intratumoral CV8102 in cMEL, cSCC, hnSCC, and ACC. U.S. National Institutes of Health. | |||||
| REF 8 | ClinicalTrials.gov (NCT03934359) A Study to Evaluate the Safety, Tolerability of DN1508052-01 in Advanced Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 9 | Clinical pipeline report, company report or official report of GlaxoSmithKline | |||||
| REF 10 | Clinical pipeline report, company report or official report of the Pharmaceutical Research and Manufacturers of America (PhRMA) | |||||
| REF 11 | ClinicalTrials.gov (NCT04460456) A Study of SBT6050 Alone and in Combination With Pembrolizumab in Patients With Advanced HER2 Expressing Solid Tumors. U.S. National Institutes of Health. | |||||
| REF 12 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800030038) | |||||
| REF 13 | ClinicalTrials.gov (NCT01666444) VTX-2337 and Pegylated Liposomal Doxorubicin (PLD) in Patients With Recurrent or Persistent Epithelial Ovarian, Fallopian Tube or Primary Peritoneal Cancer. U.S. National Institutes of Health. | |||||
| REF 14 | Clinical pipeline report, company report or official report of Idera Pharmaceuticals. | |||||
| REF 15 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2023. Adis Insight | |||||
| REF 16 | TLR agonists as vaccine adjuvants: comparison of CpG ODN and Resiquimod (R-848).Vaccine.2005 Nov 1;23(45):5263-70. | |||||
| REF 17 | 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. 2020 Sep 24;63(18):10188-10203. | |||||
| REF 18 | Clinical pipeline report, company report or official report of Nektar Therapeutics. | |||||
| REF 19 | Coley Pharmaceutical Group Diversifies Pipeline with First-in-Class TLR Antagonist for the Treatment of Systemic Lupus Erythematosus. Lupus Foundation of America, Inc. 2007. | |||||
| REF 20 | Clinical pipeline report, company report or official report of CureVac. | |||||
| REF 21 | Clinical pipeline report, company report or official report of Shanghai De Novo Pharmatech. | |||||
| REF 22 | Clinical pipeline report, company report or official report of Silverback Therapeutics. | |||||
| REF 23 | VTX-1463, a novel TLR8 agonist for the treatment of allergic rhinitis. Expert Opin Investig Drugs. 2011 Jul;20(7):981-6. | |||||
| REF 24 | Clinical pipeline report, company report or official report of Idera Pharmaceuticals. | |||||
| REF 25 | Oligodeoxynucleotide inhibition of Toll-like receptors 3, 7, 8, and 9 suppresses cytokine production in a human rheumatoid arthritis model. Eur J Immunol. 2016 Mar;46(3):772-81. | |||||
| REF 26 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Target id: 1758). | |||||
| REF 27 | Toll-like receptor 8 senses degradation products of single-stranded RNA. Nat Struct Mol Biol. 2015 Feb;22(2):109-15. | |||||
| REF 28 | Structural reorganization of the Toll-like receptor 8 dimer induced by agonistic ligands. Science. 2013 Mar 22;339(6126):1426-9. | |||||
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