Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT8QPYXZ)

• DOT Name: Toll-like receptor 3 (TLR3)
• Synonyms: CD antigen CD283
• Gene Name: TLR3
• Related Disease: Immunodeficiency 83, susceptibility to viral infections
• UniProt ID: TLR3_HUMAN
• PDB ID: 1ZIW; 2A0Z; 2MK9; 2MKA; 3ULU; 3ULV; 5GS0; 7C76; 7WV3; 7WV4; 7WV5; 7WVE; 7WVF; 7WVJ; 8AR1
• Pfam ID: PF13516 ; PF13855 ; PF01582 ; PF17968
• Sequence:
  MRQTLPCIYFWGGLLPFGMLCASSTTKCTVSHEVADCSHLKLTQVPDDLPTNITVLNLTH
  NQLRRLPAANFTRYSQLTSLDVGFNTISKLEPELCQKLPMLKVLNLQHNELSQLSDKTFA
  FCTNLTELHLMSNSIQKIKNNPFVKQKNLITLDLSHNGLSSTKLGTQVQLENLQELLLSN
  NKIQALKSEELDIFANSSLKKLELSSNQIKEFSPGCFHAIGRLFGLFLNNVQLGPSLTEK
  LCLELANTSIRNLSLSNSQLSTTSNTTFLGLKWTNLTMLDLSYNNLNVVGNDSFAWLPQL
  EYFFLEYNNIQHLFSHSLHGLFNVRYLNLKRSFTKQSISLASLPKIDDFSFQWLKCLEHL
  NMEDNDIPGIKSNMFTGLINLKYLSLSNSFTSLRTLTNETFVSLAHSPLHILNLTKNKIS
  KIESDAFSWLGHLEVLDLGLNEIGQELTGQEWRGLENIFEIYLSYNKYLQLTRNSFALVP
  SLQRLMLRRVALKNVDSSPSPFQPLRNLTILDLSNNNIANINDDMLEGLEKLEILDLQHN
  NLARLWKHANPGGPIYFLKGLSHLHILNLESNGFDEIPVEVFKDLFELKIIDLGLNNLNT
  LPASVFNNQVSLKSLNLQKNLITSVEKKVFGPAFRNLTELDMRFNPFDCTCESIAWFVNW
  INETHTNIPELSSHYLCNTPPHYHGFPVRLFDTSSCKDSAPFELFFMINTSILLIFIFIV
  LLIHFEGWRISFYWNVSVHRVLGFKEIDRQTEQFEYAAYIIHAYKDKDWVWEHFSSMEKE
  DQSLKFCLEERDFEAGVFELEAIVNSIKRSRKIIFVITHHLLKDPLCKRFKVHHAVQQAI
  EQNLDSIILVFLEEIPDYKLNHALCLRRGMFKSHCILNWPVQKERIGAFRHKLQVALGSK
  NSVH
• 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. TLR3 is a nucleotide-sensing TLR which is activated by double-stranded RNA, a sign of viral infection. Acts via the adapter TRIF/TICAM1, leading to NF-kappa-B activation, IRF3 nuclear translocation, cytokine secretion and the inflammatory response.
• Tissue Specificity: Expressed at high level in placenta and pancreas. Also detected in CD11c+ immature dendritic cells. Only expressed in dendritic cells and not in other leukocytes, including monocyte precursors. TLR3 is the TLR that is expressed most strongly in the brain, especially in astrocytes, glia, and neurons.
• KEGG Pathway:
  Necroptosis (hsa04217)
  Toll-like receptor sig.ling pathway (hsa04620)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Toll Like Receptor 3 (TLR3) Cascade (R-HSA-168164)
  TICAM1, RIP1-mediated IKK complex recruitment (R-HSA-168927)
  RIP-mediated NFkB activation via ZBP1 (R-HSA-1810476)
  TLR3 deficiency - HSE (R-HSA-5602410)
  UNC93B1 deficiency - HSE (R-HSA-5602415)
  TICAM1 deficiency - HSE (R-HSA-5602566)
  TRAF3 deficiency - HSE (R-HSA-5602571)
  TLR3-mediated TICAM1-dependent programmed cell death (R-HSA-9013957)
  TICAM1-dependent activation of IRF3/IRF7 (R-HSA-9013973)
  TICAM1,TRAF6-dependent induction of TAK1 complex (R-HSA-9014325)
  Trafficking and processing of endosomal TLR (R-HSA-1679131)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 83, susceptibility to viral infections	DISKOLA0	Limited	Unknown	[1]

This DOT Affected the Drug Response of 1 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Aspirin	DM672AH	Approved	Toll-like receptor 3 (TLR3) affects the response to substance of Aspirin.	[23]

21 Drug(s) Affected the Gene/Protein Processing of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Toll-like receptor 3 (TLR3).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Toll-like receptor 3 (TLR3).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Toll-like receptor 3 (TLR3).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Toll-like receptor 3 (TLR3).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Toll-like receptor 3 (TLR3).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Toll-like receptor 3 (TLR3).	[7]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Toll-like receptor 3 (TLR3).	[8]
Calcitriol	DM8ZVJ7	Approved	Calcitriol increases the expression of Toll-like receptor 3 (TLR3).	[9]
Testosterone	DM7HUNW	Approved	Testosterone increases the expression of Toll-like receptor 3 (TLR3).	[10]
Triclosan	DMZUR4N	Approved	Triclosan decreases the expression of Toll-like receptor 3 (TLR3).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate increases the expression of Toll-like receptor 3 (TLR3).	[12]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Toll-like receptor 3 (TLR3).	[13]
Dexamethasone	DMMWZET	Approved	Dexamethasone decreases the expression of Toll-like receptor 3 (TLR3).	[14]
Folic acid	DMEMBJC	Approved	Folic acid decreases the expression of Toll-like receptor 3 (TLR3).	[15]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Toll-like receptor 3 (TLR3).	[16]
Ethanol	DMDRQZU	Approved	Ethanol increases the expression of Toll-like receptor 3 (TLR3).	[17]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of Toll-like receptor 3 (TLR3).	[18]
Epigallocatechin gallate	DMCGWBJ	Phase 3	Epigallocatechin gallate increases the expression of Toll-like receptor 3 (TLR3).	[19]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Toll-like receptor 3 (TLR3).	[20]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Toll-like receptor 3 (TLR3).	[11]
Phencyclidine	DMQBEYX	Investigative	Phencyclidine increases the expression of Toll-like receptor 3 (TLR3).	[22]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the methylation of Toll-like receptor 3 (TLR3).	[21]

References

• [1] TLR3 deficiency in patients with herpes simplex encephalitis. Science. 2007 Sep 14;317(5844):1522-7. doi: 10.1126/science.1139522.
• [2] Integrative omics data analyses of repeated dose toxicity of valproic acid in vitro reveal new mechanisms of steatosis induction. Toxicology. 2018 Jan 15;393:160-170.
• [3] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [4] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [5] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Essential role of cell cycle regulatory genes p21 and p27 expression in inhibition of breast cancer cells by arsenic trioxide. Med Oncol. 2011 Dec;28(4):1225-54.
• [9] Role of calcitriol and cortisol on human adipocyte proliferation and oxidative and inflammatory stress: a microarray study. J Nutrigenet Nutrigenomics. 2008;1(1-2):30-48. doi: 10.1159/000109873. Epub 2007 Oct 16.
• [10] Effects of 1alpha,25 dihydroxyvitamin D3 and testosterone on miRNA and mRNA expression in LNCaP cells. Mol Cancer. 2011 May 18;10:58.
• [11] Primary Human Hepatocyte Spheroids as Tools to Study the Hepatotoxic Potential of Non-Pharmaceutical Chemicals. Int J Mol Sci. 2021 Oct 12;22(20):11005. doi: 10.3390/ijms222011005.
• [12] Functional gene expression profile underlying methotrexate-induced senescence in human colon cancer cells. Tumour Biol. 2011 Oct;32(5):965-76.
• [13] p53 regulates Toll-like receptor 3 expression and function in human epithelial cell lines. Mol Cell Biol. 2008 Nov;28(21):6557-67. doi: 10.1128/MCB.01202-08. Epub 2008 Sep 8.
• [14] Glucocorticoid regulation of human eosinophil gene expression. J Steroid Biochem Mol Biol. 2003 Mar;84(4):441-52. doi: 10.1016/s0960-0760(03)00065-7.
• [15] Folic acid modulates cancer-associated micro RNAs and inflammatory mediators in neoplastic and non-neoplastic colonic cells in a different way. Mol Nutr Food Res. 2017 Dec;61(12). doi: 10.1002/mnfr.201700260. Epub 2017 Nov 9.
• [16] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [17] Chronic ethanol exposure induces neuroinflammation in H4 cells through TLR3 / NF-B pathway and anxiety-like behavior in male C57BL/6 mice. Toxicology. 2020 Dec 15;446:152625. doi: 10.1016/j.tox.2020.152625. Epub 2020 Nov 5.
• [18] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [19] Application of the adverse outcome pathway concept for investigating developmental neurotoxicity potential of Chinese herbal medicines by using human neural progenitor cells in vitro. Cell Biol Toxicol. 2023 Feb;39(1):319-343. doi: 10.1007/s10565-022-09730-4. Epub 2022 Jun 15.
• [20] Inhibition of BRD4 attenuates tumor cell self-renewal and suppresses stem cell signaling in MYC driven medulloblastoma. Oncotarget. 2014 May 15;5(9):2355-71.
• [21] Expression and DNA methylation changes in human breast epithelial cells after bisphenol A exposure. Int J Oncol. 2012 Jul;41(1):369-77.
• [22] Microarray Analysis of Gene Expression Alteration in Human Middle Ear Epithelial Cells Induced by Asian Sand Dust. Clin Exp Otorhinolaryngol. 2015 Dec;8(4):345-53. doi: 10.3342/ceo.2015.8.4.345. Epub 2015 Nov 10.
• [23] Role of Toll-like Receptor 3 Variants in Aspirin-Exacerbated Respiratory Disease. Allergy Asthma Immunol Res. 2011 Apr;3(2):123-7. doi: 10.4168/aair.2011.3.2.123. Epub 2010 Oct 14.