Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTEJRL9C)

• DOT Name: Toll-like receptor 8 (TLR8)
• Synonyms: CD antigen CD288
• Gene Name: TLR8
• Related Disease: Immunodeficiency 98 with autoinflammation, X-linked
• UniProt ID: TLR8_HUMAN
• PDB ID: 3W3G ; 3W3J ; 3W3K ; 3W3L ; 3W3M ; 3W3N ; 3WN4 ; 4QBZ ; 4QC0 ; 4R07 ; 4R08 ; 4R09 ; 4R0A ; 4R6A ; 5AWA ; 5AWB ; 5AWC ; 5AWD ; 5AZ5 ; 5HDH ; 5WYX ; 5WYZ ; 5Z14 ; 5Z15 ; 6KYA ; 6TY5 ; 6V9U ; 6WML ; 6ZJZ ; 7CRF ; 7R52 ; 7R53 ; 7R54 ; 7RC9 ; 7YTX ; 8PFI
• Pfam ID: PF13855 ; PF01582
• Sequence:
  MENMFLQSSMLTCIFLLISGSCELCAEENFSRSYPCDEKKQNDSVIAECSNRRLQEVPQT
  VGKYVTELDLSDNFITHITNESFQGLQNLTKINLNHNPNVQHQNGNPGIQSNGLNITDGA
  FLNLKNLRELLLEDNQLPQIPSGLPESLTELSLIQNNIYNITKEGISRLINLKNLYLAWN
  CYFNKVCEKTNIEDGVFETLTNLELLSLSFNSLSHVPPKLPSSLRKLFLSNTQIKYISEE
  DFKGLINLTLLDLSGNCPRCFNAPFPCVPCDGGASINIDRFAFQNLTQLRYLNLSSTSLR
  KINAAWFKNMPHLKVLDLEFNYLVGEIASGAFLTMLPRLEILDLSFNYIKGSYPQHINIS
  RNFSKLLSLRALHLRGYVFQELREDDFQPLMQLPNLSTINLGINFIKQIDFKLFQNFSNL
  EIIYLSENRISPLVKDTRQSYANSSSFQRHIRKRRSTDFEFDPHSNFYHFTRPLIKPQCA
  AYGKALDLSLNSIFFIGPNQFENLPDIACLNLSANSNAQVLSGTEFSAIPHVKYLDLTNN
  RLDFDNASALTELSDLEVLDLSYNSHYFRIAGVTHHLEFIQNFTNLKVLNLSHNNIYTLT
  DKYNLESKSLVELVFSGNRLDILWNDDDNRYISIFKGLKNLTRLDLSLNRLKHIPNEAFL
  NLPASLTELHINDNMLKFFNWTLLQQFPRLELLDLRGNKLLFLTDSLSDFTSSLRTLLLS
  HNRISHLPSGFLSEVSSLKHLDLSSNLLKTINKSALETKTTTKLSMLELHGNPFECTCDI
  GDFRRWMDEHLNVKIPRLVDVICASPGDQRGKSIVSLELTTCVSDVTAVILFFFTFFITT
  MVMLAALAHHLFYWDVWFIYNVCLAKVKGYRSLSTSQTFYDAYISYDTKDASVTDWVINE
  LRYHLEESRDKNVLLCLEERDWDPGLAIIDNLMQSINQSKKTVFVLTKKYAKSWNFKTAF
  YLALQRLMDENMDVIIFILLEPVLQHSQYLRLRQRICKSSILQWPDNPKAEGLFWQTLRN
  VVLTENDSRYNNMYVDSIKQY
• Function: Endosomal receptor that plays a key role in innate and adaptive immunity. Controls host immune response against pathogens through recognition of RNA degradation products specific to microorganisms that are initially processed by RNASET2. Recognizes GU-rich single-stranded RNA (GU-rich RNA) derived from SARS-CoV-2, SARS-CoV-1 and HIV-1 viruses. Upon binding to agonists, undergoes dimerization that brings TIR domains from the two molecules into direct contact, leading to the recruitment of TIR-containing downstream adapter MYD88 through homotypic interaction. In turn, the Myddosome signaling complex is formed involving IRAK4, IRAK1, TRAF6, TRAF3 leading to activation of downstream transcription factors NF-kappa-B and IRF7 to induce pro-inflammatory cytokines and interferons, respectively.
• Tissue Specificity: Expressed in myeloid dendritic cells, monocytes, and monocyte-derived dendritic cells.
• KEGG Pathway:
  Neutrophil extracellular trap formation (hsa04613)
  Toll-like receptor sig.ling pathway (hsa04620)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  Toll Like Receptor 7/8 (TLR7/8) Cascade (R-HSA-168181)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  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 98 with autoinflammation, X-linked	DIS3NZSE	Limited	Unknown	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Toll-like receptor 8 (TLR8).	[2]
Arsenic	DMTL2Y1	Approved	Arsenic decreases the expression of Toll-like receptor 8 (TLR8).	[3]
Malathion	DMXZ84M	Approved	Malathion increases the expression of Toll-like receptor 8 (TLR8).	[4]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine decreases the activity of Toll-like receptor 8 (TLR8).	[5]
Nabiximols	DMHKJ5I	Phase 3	Nabiximols decreases the expression of Toll-like receptor 8 (TLR8).	[6]
PF-4878691	DM24I0N	Phase 2	PF-4878691 increases the activity of Toll-like receptor 8 (TLR8).	[7]

References

• [1] Immunodeficiency and bone marrow failure with mosaic and germline TLR8 gain of function. Blood. 2021 May 6;137(18):2450-2462. doi: 10.1182/blood.2020009620.
• [2] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [3] Transcriptomics and methylomics of CD4-positive T cells in arsenic-exposed women. Arch Toxicol. 2017 May;91(5):2067-2078. doi: 10.1007/s00204-016-1879-4. Epub 2016 Nov 12.
• [4] Malathion induced cancer-linked gene expression in human lymphocytes. Environ Res. 2020 Mar;182:109131. doi: 10.1016/j.envres.2020.109131. Epub 2020 Jan 10.
• [5] HCV RNA Activates APCs via TLR7/TLR8 While Virus Selectively Stimulates Macrophages Without Inducing Antiviral Responses. Sci Rep. 2016 Jul 7;6:29447. doi: 10.1038/srep29447.
• [6] Clinical response to Nabiximols correlates with the downregulation of immune pathways in multiple sclerosis. Eur J Neurol. 2018 Jul;25(7):934-e70. doi: 10.1111/ene.13623. Epub 2018 Apr 16.
• [7] Chloroquine modulates HIV-1-induced plasmacytoid dendritic cell alpha interferon: implication for T-cell activation. Antimicrob Agents Chemother. 2010 Feb;54(2):871-81. doi: 10.1128/AAC.01246-09. Epub 2009 Nov 30.