Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFZ45HX)

• DOT Name: Toll-like receptor 9 (TLR9)
• Synonyms: CD antigen CD289
• Gene Name: TLR9
• UniProt ID: TLR9_HUMAN
• PDB ID: 8AR3
• Pfam ID: PF18837 ; PF13516 ; PF13855 ; PF01582
• Sequence:
  MGFCRSALHPLSLLVQAIMLAMTLALGTLPAFLPCELQPHGLVNCNWLFLKSVPHFSMAA
  PRGNVTSLSLSSNRIHHLHDSDFAHLPSLRHLNLKWNCPPVGLSPMHFPCHMTIEPSTFL
  AVPTLEELNLSYNNIMTVPALPKSLISLSLSHTNILMLDSASLAGLHALRFLFMDGNCYY
  KNPCRQALEVAPGALLGLGNLTHLSLKYNNLTVVPRNLPSSLEYLLLSYNRIVKLAPEDL
  ANLTALRVLDVGGNCRRCDHAPNPCMECPRHFPQLHPDTFSHLSRLEGLVLKDSSLSWLN
  ASWFRGLGNLRVLDLSENFLYKCITKTKAFQGLTQLRKLNLSFNYQKRVSFAHLSLAPSF
  GSLVALKELDMHGIFFRSLDETTLRPLARLPMLQTLRLQMNFINQAQLGIFRAFPGLRYV
  DLSDNRISGASELTATMGEADGGEKVWLQPGDLAPAPVDTPSSEDFRPNCSTLNFTLDLS
  RNNLVTVQPEMFAQLSHLQCLRLSHNCISQAVNGSQFLPLTGLQVLDLSHNKLDLYHEHS
  FTELPRLEALDLSYNSQPFGMQGVGHNFSFVAHLRTLRHLSLAHNNIHSQVSQQLCSTSL
  RALDFSGNALGHMWAEGDLYLHFFQGLSGLIWLDLSQNRLHTLLPQTLRNLPKSLQVLRL
  RDNYLAFFKWWSLHFLPKLEVLDLAGNQLKALTNGSLPAGTRLRRLDVSCNSISFVAPGF
  FSKAKELRELNLSANALKTVDHSWFGPLASALQILDVSANPLHCACGAAFMDFLLEVQAA
  VPGLPSRVKCGSPGQLQGLSIFAQDLRLCLDEALSWDCFALSLLAVALGLGVPMLHHLCG
  WDLWYCFHLCLAWLPWRGRQSGRDEDALPYDAFVVFDKTQSAVADWVYNELRGQLEECRG
  RWALRLCLEERDWLPGKTLFENLWASVYGSRKTLFVLAHTDRVSGLLRASFLLAQQRLLE
  DRKDVVVLVILSPDGRRSRYVRLRQRLCRQSVLLWPHQPSGQRSFWAQLGMALTRDNHHF
  YNRNFCQGPTAE
• 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. TLR9 is a nucleotide-sensing TLR which is activated by unmethylated cytidine-phosphate-guanosine (CpG) dinucleotides. Acts via MYD88 and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory response. Controls lymphocyte response to Helicobacter infection. Upon CpG stimulation, induces B-cell proliferation, activation, survival and antibody production.
• Tissue Specificity: Highly expressed in spleen, lymph node, tonsil and peripheral blood leukocytes, especially in plasmacytoid pre-dendritic cells. Levels are much lower in monocytes and CD11c+ immature dendritic cells. Also detected in lung and liver.
• KEGG Pathway:
  Toll-like receptor sig.ling pathway (hsa04620)
  Salmonella infection (hsa05132)
  Chagas disease (hsa05142)
  African trypanosomiasis (hsa05143)
  Malaria (hsa05144)
  Tuberculosis (hsa05152)
  Measles (hsa05162)
  Herpes simplex virus 1 infection (hsa05168)
  PD-L1 expression and PD-1 checkpoint pathway in cancer (hsa05235)
• Reactome Pathway:
  Trafficking and processing of endosomal TLR (R-HSA-1679131)
  Toll Like Receptor 9 (TLR9) Cascade (R-HSA-168138)
  Potential therapeutics for SARS (R-HSA-9679191)
  TRAF6 mediated IRF7 activation in TLR7/8 or 9 signaling (R-HSA-975110)
  TRAF6 mediated induction of NFkB and MAP kinases upon TLR7/8 or 9 activation (R-HSA-975138)
  MyD88 dependent cascade initiated on endosome (R-HSA-975155)
  PI3K Cascade (R-HSA-109704)

Molecular Interaction Atlas (MIA) of This DOT

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Hydroxychloroquine	DMSIVND	Approved	Hydroxychloroquine decreases the expression of Toll-like receptor 9 (TLR9).	[1]
Chloroquine	DMSI5CB	Phase 3 Trial	Chloroquine increases the expression of Toll-like receptor 9 (TLR9).	[2]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the mutagenesis of Toll-like receptor 9 (TLR9).	[3]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Toll-like receptor 9 (TLR9).	[4]

References

• [1] Antagonist-mediated down-regulation of Toll-like receptors increases the prevalence of human papillomavirus infection in systemic lupus erythematosus. Arthritis Res Ther. 2012 Apr 18;14(2):R80. doi: 10.1186/ar3803.
• [2] Chloroquine has tumor-inhibitory and tumor-promoting effects in triple-negative breast cancer. Oncol Lett. 2013 Dec;6(6):1665-1672. doi: 10.3892/ol.2013.1602. Epub 2013 Oct 4.
• [3] Exome-wide mutation profile in benzo[a]pyrene-derived post-stasis and immortal human mammary epithelial cells. Mutat Res Genet Toxicol Environ Mutagen. 2014 Dec;775-776:48-54. doi: 10.1016/j.mrgentox.2014.10.011. Epub 2014 Nov 4.
• [4] Toll-like receptor 9 mediates paraquat-induced acute lung injury: an in vitro and in vivo study. Life Sci. 2017 Jun 1;178:109-118. doi: 10.1016/j.lfs.2017.03.021. Epub 2017 Mar 29.