Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZC7SIM)

• DOT Name: Sialic acid-binding Ig-like lectin 9 (SIGLEC9)
• Synonyms: Siglec-9; CDw329; Protein FOAP-9; CD antigen CD329
• Gene Name: SIGLEC9
• Related Disease:
  Adult glioblastoma
  Arthritis
  Glioblastoma multiforme
  Rheumatoid arthritis
  Acute liver failure
  Advanced cancer
  Arteriosclerosis
  Asthma
  Atherosclerosis
  Carcinoma
  Chikungunya virus infection
  Chronic obstructive pulmonary disease
  Colorectal carcinoma
  Leukemia
  Melanoma
  Non-small-cell lung cancer
  Pulmonary disease
  Pulmonary emphysema
  Neoplasm
  Chronic hepatitis B virus infection
  Streptococcal B infection
• UniProt ID: SIGL9_HUMAN
• Pfam ID: PF00047 ; PF07686
• Sequence:
  MLLLLLPLLWGRERAEGQTSKLLTMQSSVTVQEGLCVHVPCSFSYPSHGWIYPGPVVHGY
  WFREGANTDQDAPVATNNPARAVWEETRDRFHLLGDPHTKNCTLSIRDARRSDAGRYFFR
  MEKGSIKWNYKHHRLSVNVTALTHRPNILIPGTLESGCPQNLTCSVPWACEQGTPPMISW
  IGTSVSPLDPSTTRSSVLTLIPQPQDHGTSLTCQVTFPGASVTTNKTVHLNVSYPPQNLT
  MTVFQGDGTVSTVLGNGSSLSLPEGQSLRLVCAVDAVDSNPPARLSLSWRGLTLCPSQPS
  NPGVLELPWVHLRDAAEFTCRAQNPLGSQQVYLNVSLQSKATSGVTQGVVGGAGATALVF
  LSFCVIFVVVRSCRKKSARPAAGVGDTGIEDANAVRGSASQGPLTEPWAEDSPPDQPPPA
  SARSSVGEGELQYASLSFQMVKPWDSRGQEATDTEYSEIKIHR
• Function: Putative adhesion molecule that mediates sialic-acid dependent binding to cells. Preferentially binds to alpha-2,3- or alpha-2,6-linked sialic acid. The sialic acid recognition site may be masked by cis interactions with sialic acids on the same cell surface.
• Tissue Specificity: Expressed by peripheral blood leukocytes (neutrophils and monocytes but not eosinophils). Found in liver, fetal liver, bone marrow, placenta, spleen and in lower levels in skeletal muscle, fetal brain, stomach, lung, thymus, prostate, brain, mammary, adrenal gland, colon, trachea, cerebellum, testis, small intestine and spinal cordon.
• KEGG Pathway: Neutrophil extracellular trap formation (hsa04613)
• Reactome Pathway:
  Neutrophil degranulation (R-HSA-6798695)
  Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

21 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Adult glioblastoma	DISVP4LU	Definitive	Biomarker	[1]
Arthritis	DIST1YEL	Definitive	Biomarker	[2]
Glioblastoma multiforme	DISK8246	Definitive	Biomarker	[1]
Rheumatoid arthritis	DISTSB4J	Definitive	Biomarker	[2]
Acute liver failure	DIS5EZKX	Strong	Biomarker	[3]
Advanced cancer	DISAT1Z9	Strong	Biomarker	[4]
Arteriosclerosis	DISK5QGC	Strong	Altered Expression	[5]
Asthma	DISW9QNS	Strong	Biomarker	[6]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[5]
Carcinoma	DISH9F1N	Strong	Biomarker	[7]
Chikungunya virus infection	DISDXEHY	Strong	Altered Expression	[8]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Genetic Variation	[9]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[10]
Leukemia	DISNAKFL	Strong	Biomarker	[11]
Melanoma	DIS1RRCY	Strong	Altered Expression	[12]
Non-small-cell lung cancer	DIS5Y6R9	Strong	Altered Expression	[10]
Pulmonary disease	DIS6060I	Strong	Biomarker	[6]
Pulmonary emphysema	DIS5M7HZ	moderate	Genetic Variation	[9]
Neoplasm	DISZKGEW	Disputed	Biomarker	[12]
Chronic hepatitis B virus infection	DISHL4NT	Limited	Biomarker	[13]
Streptococcal B infection	DISN80QT	Limited	Biomarker	[14]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the methylation of Sialic acid-binding Ig-like lectin 9 (SIGLEC9).	[15]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Sialic acid-binding Ig-like lectin 9 (SIGLEC9).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of Sialic acid-binding Ig-like lectin 9 (SIGLEC9).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Sialic acid-binding Ig-like lectin 9 (SIGLEC9).	[18]

References

• [1] Glycan modification of glioblastoma-derived extracellular vesicles enhances receptor-mediated targeting of dendritic cells.J Extracell Vesicles. 2019 Aug 9;8(1):1648995. doi: 10.1080/20013078.2019.1648995. eCollection 2019.
• [2] Siglec-9 is upregulated in rheumatoid arthritis and suppresses collagen-induced arthritis through reciprocal regulation of Th17-/Treg-cell differentiation.Scand J Immunol. 2017 Jun;85(6):433-440. doi: 10.1111/sji.12543.
• [3] Secreted Ectodomain of SIGLEC-9 and MCP-1 Synergistically Improve Acute Liver Failure in Rats by Altering Macrophage Polarity.Sci Rep. 2017 Mar 8;7:44043. doi: 10.1038/srep44043.
• [4] Sugar Free: Novel Immunotherapeutic Approaches Targeting Siglecs and Sialic Acids to Enhance Natural Killer Cell Cytotoxicity Against Cancer.Front Immunol. 2019 May 9;10:1047. doi: 10.3389/fimmu.2019.01047. eCollection 2019.
• [5] Immunoregulatory Siglec ligands are abundant in human and mouse aorta and are up-regulated by high glucose.Life Sci. 2019 Jan 1;216:189-199. doi: 10.1016/j.lfs.2018.11.049. Epub 2018 Nov 22.
• [6] Targeting Neutrophils in Severe Asthma via Siglec-9.Int Arch Allergy Immunol. 2018;175(1-2):5-15. doi: 10.1159/000484873. Epub 2018 Jan 6.
• [7] Engagement of myelomonocytic Siglecs by tumor-associated ligands modulates the innate immune response to cancer.Proc Natl Acad Sci U S A. 2014 Sep 30;111(39):14211-6. doi: 10.1073/pnas.1409580111. Epub 2014 Sep 15.
• [8] Oxidative damage markers and inflammatory cytokines are altered in patients suffering with post-chikungunya persisting polyarthralgia.Free Radic Res. 2018 Aug;52(8):887-895. doi: 10.1080/10715762.2018.1489131. Epub 2018 Jul 23.
• [9] Influence of SIGLEC9 polymorphisms on COPD phenotypes including exacerbation frequency.Respirology. 2017 May;22(4):684-690. doi: 10.1111/resp.12952. Epub 2016 Nov 22.
• [10] Self-associated molecular patterns mediate cancer immune evasion by engaging Siglecs on T cells.J Clin Invest. 2018 Nov 1;128(11):4912-4923. doi: 10.1172/JCI120612. Epub 2018 Sep 24.
• [11] The membrane-proximal immunoreceptor tyrosine-based inhibitory motif is critical for the inhibitory signaling mediated by Siglecs-7 and -9, CD33-related Siglecs expressed on human monocytes and NK cells.J Immunol. 2004 Dec 1;173(11):6841-9. doi: 10.4049/jimmunol.173.11.6841.
• [12] Siglec-9 Regulates an Effector Memory CD8(+) T-cell Subset That Congregates in the Melanoma Tumor Microenvironment.Cancer Immunol Res. 2019 May;7(5):707-718. doi: 10.1158/2326-6066.CIR-18-0505. Epub 2019 Apr 15.
• [13] Decreased Siglec-9 Expression on Natural Killer Cell Subset Associated With Persistent HBV Replication.Front Immunol. 2018 May 30;9:1124. doi: 10.3389/fimmu.2018.01124. eCollection 2018.
• [14] Implication of Soluble Forms of Cell Adhesion Molecules in Infectious Disease and Tumor: Insights from Transgenic Animal Models.Int J Mol Sci. 2018 Jan 13;19(1):239. doi: 10.3390/ijms19010239.
• [15] 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.
• [16] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [17] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [18] Sulforaphane-induced apoptosis in human leukemia HL-60 cells through extrinsic and intrinsic signal pathways and altering associated genes expression assayed by cDNA microarray. Environ Toxicol. 2017 Jan;32(1):311-328.