Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTNWSQA9)

• DOT Name: Sialoadhesin (SIGLEC1)
• Synonyms: Sialic acid-binding Ig-like lectin 1; Siglec-1; CD antigen CD169
• Gene Name: SIGLEC1
• Related Disease:
  Non-insulin dependent diabetes
  Respiratory syncytial virus infection
  Advanced cancer
  Anemia
  Autoimmune disease
  Carcinoma of esophagus
  Diphtheria
  Esophageal cancer
  Graves disease
  Hepatitis B virus infection
  Hepatitis C virus infection
  Influenza
  Kaposi sarcoma
  Liver cirrhosis
  Lupus
  Multiple sclerosis
  Neoplasm of esophagus
  Nephropathy
  Nervous system inflammation
  Non-alcoholic fatty liver disease
  Prostate cancer
  Prostate carcinoma
  Prostate neoplasm
  Pulmonary tuberculosis
  Systemic lupus erythematosus
  Systemic sclerosis
  Tuberculosis
  Bladder cancer
  Head-neck squamous cell carcinoma
  Neoplasm
  Plasma cell myeloma
  Urinary bladder cancer
  Urinary bladder neoplasm
  Endometrium neoplasm
  Asthma
  Breast cancer
  Breast carcinoma
  Colitis
  Coronary atherosclerosis
  Ebola virus infection
  leukaemia
  Leukemia
  Melanoma
  Rheumatoid arthritis
• UniProt ID: SN_HUMAN
• Pfam ID: PF08205 ; PF07679 ; PF00047 ; PF13895 ; PF07686
• Sequence:
  MGFLPKLLLLASFFPAGQASWGVSSPQDVQGVKGSCLLIPCIFSFPADVEVPDGITAIWY
  YDYSGQRQVVSHSADPKLVEARFRGRTEFMGNPEHRVCNLLLKDLQPEDSGSYNFRFEIS
  EVNRWSDVKGTLVTVTEEPRVPTIASPVELLEGTEVDFNCSTPYVCLQEQVRLQWQGQDP
  ARSVTFNSQKFEPTGVGHLETLHMAMSWQDHGRILRCQLSVANHRAQSEIHLQVKYAPKG
  VKILLSPSGRNILPGELVTLTCQVNSSYPAVSSIKWLKDGVRLQTKTGVLHLPQAAWSDA
  GVYTCQAENGVGSLVSPPISLHIFMAEVQVSPAGPILENQTVTLVCNTPNEAPSDLRYSW
  YKNHVLLEDAHSHTLRLHLATRADTGFYFCEVQNVHGSERSGPVSVVVNHPPLTPVLTAF
  LETQAGLVGILHCSVVSEPLATLVLSHGGHILASTSGDSDHSPRFSGTSGPNSLRLEIRD
  LEETDSGEYKCSATNSLGNATSTLDFHANAARLLISPAAEVVEGQAVTLSCRSGLSPTPD
  ARFSWYLNGALLHEGPGSSLLLPAASSTDAGSYHCRARDGHSASGPSSPAVLTVLYPPRQ
  PTFTTRLDLDAAGAGAGRRGLLLCRVDSDPPARLQLLHKDRVVATSLPSGGGCSTCGGCS
  PRMKVTKAPNLLRVEIHNPLLEEEGLYLCEASNALGNASTSATFNGQATVLAIAPSHTLQ
  EGTEANLTCNVSREAAGSPANFSWFRNGVLWAQGPLETVTLLPVARTDAALYACRILTEA
  GAQLSTPVLLSVLYPPDRPKLSALLDMGQGHMALFICTVDSRPLALLALFHGEHLLATSL
  GPQVPSHGRFQAKAEANSLKLEVRELGLGDSGSYRCEATNVLGSSNTSLFFQVRGAWVQV
  SPSPELQEGQAVVLSCQVHTGVPEGTSYRWYRDGQPLQESTSATLRFAAITLTQAGAYHC
  QAQAPGSATTSLAAPISLHVSYAPRHVTLTTLMDTGPGRLGLLLCRVDSDPPAQLRLLHG
  DRLVASTLQGVGGPEGSSPRLHVAVAPNTLRLEIHGAMLEDEGVYICEASNTLGQASASA
  DFDAQAVNVQVWPGATVREGQLVNLTCLVWTTHPAQLTYTWYQDGQQRLDAHSIPLPNVT
  VRDATSYRCGVGPPGRAPRLSRPITLDVLYAPRNLRLTYLLESHGGQLALVLCTVDSRPP
  AQLALSHAGRLLASSTAASVPNTLRLELRGPQPRDEGFYSCSARSPLGQANTSLELRLEG
  VRVILAPEAAVPEGAPITVTCADPAAHAPTLYTWYHNGRWLQEGPAASLSFLVATRAHAG
  AYSCQAQDAQGTRSSRPAALQVLYAPQDAVLSSFRDSRARSMAVIQCTVDSEPPAELALS
  HDGKVLATSSGVHSLASGTGHVQVARNALRLQVQDVPAGDDTYVCTAQNLLGSISTIGRL
  QVEGARVVAEPGLDVPEGAALNLSCRLLGGPGPVGNSTFAWFWNDRRLHAEPVPTLAFTH
  VARAQAGMYHCLAELPTGAAASAPVMLRVLYPPKTPTMMVFVEPEGGLRGILDCRVDSEP
  LASLTLHLGSRLVASSQPQGAPAEPHIHVLASPNALRVDIEALRPSDQGEYICSASNVLG
  SASTSTYFGVRALHRLHQFQQLLWVLGLLVGLLLLLLGLGACYTWRRRRVCKQSMGENSV
  EMAFQKETTQLIDPDAATCETSTCAPPLG
• Function: Macrophage-restricted adhesion molecule that mediates sialic-acid dependent binding to lymphocytes, including granulocytes, monocytes, natural killer cells, B-cells and CD8 T-cells. Plays a crucial role in limiting bacterial dissemination by engaging sialylated bacteria to promote effective phagocytosis and antigen presentation for the adaptive immune response. Mediates the uptake of various enveloped viruses via sialic acid recognition and subsequently induces the formation of intracellular compartments filled with virions (VCCs). In turn, enhances macrophage-to-T-cell transmission of several viruses including HIV-1 or SARS-CoV-2. Acts as an endocytic receptor mediating clathrin dependent endocytosis. Preferentially binds to alpha-2,3-linked sialic acid. Binds to SPN/CD43 on T-cells. May play a role in hemopoiesis. Plays a role in the inhibition of antiviral innate immune by promoting TBK1 degradation via TYROBP and TRIM27-mediated ubiquitination ; (Microbial infection) Facilitates viral cytoplasmic entry into activated dendritic cells via recognition of sialylated gangliosides pesent on viral membrane.
• Tissue Specificity: Expressed by macrophages in various tissues. High levels are found in spleen, lymph node, perivascular macrophages in brain and lower levels in bone marrow, liver Kupffer cells and lamina propria of colon and lung. Also expressed by inflammatory macrophages in rheumatoid arthritis.
• KEGG Pathway: Cell adhesion molecules (hsa04514)
• Reactome Pathway: Immunoregulatory interactions between a Lymphoid and a non-Lymphoid cell (R-HSA-198933)

Molecular Interaction Atlas (MIA) of This DOT

44 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Non-insulin dependent diabetes	DISK1O5Z	Definitive	Altered Expression	[1]
Respiratory syncytial virus infection	DIS7FWHY	Definitive	Biomarker	[2]
Advanced cancer	DISAT1Z9	Strong	Altered Expression	[3]
Anemia	DISTVL0C	Strong	Biomarker	[4]
Autoimmune disease	DISORMTM	Strong	Biomarker	[5]
Carcinoma of esophagus	DISS6G4D	Strong	Altered Expression	[3]
Diphtheria	DISZWM55	Strong	Biomarker	[6]
Esophageal cancer	DISGB2VN	Strong	Altered Expression	[3]
Graves disease	DISU4KOQ	Strong	Altered Expression	[7]
Hepatitis B virus infection	DISLQ2XY	Strong	Biomarker	[8]
Hepatitis C virus infection	DISQ0M8R	Strong	Altered Expression	[9]
Influenza	DIS3PNU3	Strong	Biomarker	[10]
Kaposi sarcoma	DISC1H1Z	Strong	Altered Expression	[11]
Liver cirrhosis	DIS4G1GX	Strong	Biomarker	[8]
Lupus	DISOKJWA	Strong	Biomarker	[12]
Multiple sclerosis	DISB2WZI	Strong	Altered Expression	[13]
Neoplasm of esophagus	DISOLKAQ	Strong	Altered Expression	[3]
Nephropathy	DISXWP4P	Strong	Biomarker	[14]
Nervous system inflammation	DISB3X5A	Strong	Altered Expression	[13]
Non-alcoholic fatty liver disease	DISDG1NL	Strong	Altered Expression	[9]
Prostate cancer	DISF190Y	Strong	Altered Expression	[15]
Prostate carcinoma	DISMJPLE	Strong	Altered Expression	[15]
Prostate neoplasm	DISHDKGQ	Strong	Altered Expression	[15]
Pulmonary tuberculosis	DIS6FLUM	Strong	Genetic Variation	[16]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[17]
Systemic sclerosis	DISF44L6	Strong	Altered Expression	[18]
Tuberculosis	DIS2YIMD	Strong	Biomarker	[16]
Bladder cancer	DISUHNM0	moderate	Biomarker	[19]
Head-neck squamous cell carcinoma	DISF7P24	moderate	Altered Expression	[20]
Neoplasm	DISZKGEW	moderate	Altered Expression	[20]
Plasma cell myeloma	DIS0DFZ0	moderate	Biomarker	[21]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[19]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[19]
Endometrium neoplasm	DIS6OS2L	Disputed	Biomarker	[22]
Asthma	DISW9QNS	Limited	Biomarker	[23]
Breast cancer	DIS7DPX1	Limited	Biomarker	[24]
Breast carcinoma	DIS2UE88	Limited	Biomarker	[24]
Colitis	DISAF7DD	Limited	Biomarker	[25]
Coronary atherosclerosis	DISKNDYU	Limited	Biomarker	[26]
Ebola virus infection	DISJAVM1	Limited	Altered Expression	[27]
leukaemia	DISS7D1V	Limited	Altered Expression	[28]
Leukemia	DISNAKFL	Limited	Altered Expression	[28]
Melanoma	DIS1RRCY	Limited	Biomarker	[29]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[30]

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 Sialoadhesin (SIGLEC1).	[31]
Coumarin	DM0N8ZM	Investigative	Coumarin decreases the phosphorylation of Sialoadhesin (SIGLEC1).	[35]

3 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 Sialoadhesin (SIGLEC1).	[32]
Amphotericin B	DMTAJQE	Approved	Amphotericin B increases the expression of Sialoadhesin (SIGLEC1).	[33]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Sialoadhesin (SIGLEC1).	[34]

References

• [1] Differential Expression of Human Peripheral Mononuclear Cells Phenotype Markers in Type 2 Diabetic Patients and Type 2 Diabetic Patients on Metformin.Front Endocrinol (Lausanne). 2018 Oct 9;9:537. doi: 10.3389/fendo.2018.00537. eCollection 2018.
• [2] Transient Depletion of CD169(+) Cells Contributes to Impaired Early Protection and Effector CD8(+) T Cell Recruitment against Mucosal Respiratory Syncytial Virus Infection.Front Immunol. 2017 Jul 13;8:819. doi: 10.3389/fimmu.2017.00819. eCollection 2017.
• [3] High CD169 expression in lymph node macrophages predicts a favorable clinical course in patients with esophageal cancer.Pathol Int. 2018 Dec;68(12):685-693. doi: 10.1111/pin.12736. Epub 2018 Dec 5.
• [4] A Shift in Myeloid Cell Phenotype via Down Regulation of Siglec-1 in Island Macrophages of Bone Marrow Is Associated With Decreased Late Erythroblasts Seen in Anemia of Critical Illness.Front Med (Lausanne). 2019 Nov 20;6:260. doi: 10.3389/fmed.2019.00260. eCollection 2019.
• [5] Siglec-1 and -2 as potential biomarkers in autoimmune disease.Proteomics Clin Appl. 2016 Jun;10(6):635-44. doi: 10.1002/prca.201500069.
• [6] Islet macrophages are associated with islet vascular remodeling and compensatory hyperinsulinemia during diabetes.Am J Physiol Endocrinol Metab. 2019 Dec 1;317(6):E1108-E1120. doi: 10.1152/ajpendo.00248.2019. Epub 2019 Oct 1.
• [7] Sialic Acid-Binding Immunoglobulin-Like Lectin1 as a Novel Predictive Biomarker for Relapse in Graves' Disease: A Multicenter Study.Thyroid. 2018 Jan;28(1):50-59. doi: 10.1089/thy.2017.0244. Epub 2017 Nov 21.
• [8] Increased Siglec-1 expression in monocytes of patients with primary biliary cirrhosis.Immunol Invest. 2010;39(6):645-60. doi: 10.3109/08820139.2010.485625.
• [9] Altered Peripheral Blood Monocyte Phenotype and Function in Chronic Liver Disease: Implications for Hepatic Recruitment and Systemic Inflammation.PLoS One. 2016 Jun 16;11(6):e0157771. doi: 10.1371/journal.pone.0157771. eCollection 2016.
• [10] A host transcriptional signature for presymptomatic detection of infection in humans exposed to influenza H1N1 or H3N2.PLoS One. 2013;8(1):e52198. doi: 10.1371/journal.pone.0052198. Epub 2013 Jan 9.
• [11] Sialoadhesin (CD169) expression in CD14+ cells is upregulated early after HIV-1 infection and increases during disease progression.PLoS One. 2007 Feb 28;2(2):e257. doi: 10.1371/journal.pone.0000257.
• [12] Are interferon-related biomarkers advantageous for monitoring disease activity in systemic lupus erythematosus? A longitudinal benchmark study.Rheumatology (Oxford). 2017 Sep 1;56(9):1618-1626. doi: 10.1093/rheumatology/kex220.
• [13] CD169 is a marker for highly pathogenic phagocytes in multiple sclerosis.Mult Scler. 2018 Mar;24(3):290-300. doi: 10.1177/1352458517698759. Epub 2017 Mar 9.
• [14] The plasma biomarker soluble SIGLEC-1 is associated with the type I interferon transcriptional signature, ethnic background and renal disease in systemic lupus erythematosus.Arthritis Res Ther. 2018 Jul 27;20(1):152. doi: 10.1186/s13075-018-1649-1.
• [15] Reduced number of CD169(+) macrophages in pre-metastatic regional lymph nodes is associated with subsequent metastatic disease in an animal model and with poor outcome in prostate cancer patients.Prostate. 2017 Nov;77(15):1468-1477. doi: 10.1002/pros.23407. Epub 2017 Sep 7.
• [16] Polymorphisms in SIGLEC1 contribute to susceptibility to pulmonary active tuberculosis possibly through the modulation of IL-1.Infect Genet Evol. 2017 Nov;55:313-317. doi: 10.1016/j.meegid.2017.09.031. Epub 2017 Sep 28.
• [17] Osmium-Labeled Microspheres for Bead-Based Assays in Mass Cytometry.J Immunol. 2019 May 15;202(10):3103-3112. doi: 10.4049/jimmunol.1801640. Epub 2019 Apr 15.
• [18] A macrophage marker, Siglec-1, is increased on circulating monocytes in patients with systemic sclerosis and induced by type I interferons and toll-like receptor agonists.Arthritis Rheum. 2007 Mar;56(3):1010-20. doi: 10.1002/art.22382.
• [19] CD169-positive sinus macrophages in the lymph nodes determine bladder cancer prognosis.Cancer Sci. 2018 May;109(5):1723-1730. doi: 10.1111/cas.13565. Epub 2018 Apr 14.
• [20] Loss of CD169(+) Subcapsular Macrophages during Metastatic Spread of Head and Neck Squamous Cell Carcinoma.Otolaryngol Head Neck Surg. 2019 Jul;161(1):67-73. doi: 10.1177/0194599819829741. Epub 2019 Feb 12.
• [21] Clodronate-Liposome Mediated Macrophage Depletion Abrogates Multiple Myeloma Tumor Establishment In Vivo.Neoplasia. 2019 Aug;21(8):777-787. doi: 10.1016/j.neo.2019.05.006. Epub 2019 Jun 24.
• [22] Possible functions of CD169-positive sinus macrophages in lymph nodes in anti-tumor immune responses.Cancer Sci. 2017 Mar;108(3):290-295. doi: 10.1111/cas.13137. Epub 2017 Mar 7.
• [23] Asthma severity, polymorphisms in 20p13 and their interaction with tobacco smoke exposure.Pediatr Allergy Immunol. 2013 Feb;24(1):10-8. doi: 10.1111/pai.12019.
• [24] Deciphering Macrophage and Monocyte Code to Stratify Human Breast Cancer Patients.Cancer Cell. 2019 Apr 15;35(4):538-539. doi: 10.1016/j.ccell.2019.03.010.
• [25] Low Dose of Cyanidin-3-O-Glucoside Alleviated Dextran Sulfate Sodium-Induced Colitis, Mediated by CD169+ Macrophage Pathway.Inflamm Bowel Dis. 2019 Aug 20;25(9):1510-1521. doi: 10.1093/ibd/izz090.
• [26] Siglec-1 on monocytes is a potential risk marker for monitoring disease severity in coronary artery disease.Clin Biochem. 2009 Jul;42(10-11):1057-63. doi: 10.1016/j.clinbiochem.2009.02.026. Epub 2009 Mar 13.
• [27] Anti-Siglec-1 antibodies block Ebola viral uptake and decrease cytoplasmic viral entry.Nat Microbiol. 2019 Sep;4(9):1558-1570. doi: 10.1038/s41564-019-0453-2. Epub 2019 Jun 3.
• [28] CD33 (Siglec-3) Inhibitory Function: Role in the NKG2D/DAP10 Activating Pathway.J Immunol Res. 2019 Apr 15;2019:6032141. doi: 10.1155/2019/6032141. eCollection 2019.
• [29] Activation of CD8?T Cell Responses after Melanoma Antigen Targeting to CD169?Antigen Presenting Cells in Mice and Humans.Cancers (Basel). 2019 Feb 5;11(2):183. doi: 10.3390/cancers11020183.
• [30] The physiologic increase in expression of some type I IFN-inducible genes during pregnancy is not associated with improved disease activity in pregnant patients with rheumatoid arthritis.Transl Res. 2013 Jun;161(6):505-12. doi: 10.1016/j.trsl.2013.02.007. Epub 2013 Mar 16.
• [31] 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.
• [32] 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.
• [33] Differential expression of microRNAs and their predicted targets in renal cells exposed to amphotericin B and its complex with copper (II) ions. Toxicol Mech Methods. 2017 Sep;27(7):537-543. doi: 10.1080/15376516.2017.1333554. Epub 2017 Jun 8.
• [34] Identification of a transcriptomic signature of food-relevant genotoxins in human HepaRG hepatocarcinoma cells. Food Chem Toxicol. 2020 Jun;140:111297. doi: 10.1016/j.fct.2020.111297. Epub 2020 Mar 28.
• [35] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.