Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT5N1B9B)

• DOT Name: Neutrophil defensin 1 (DEFA1)
• Synonyms: Defensin, alpha 1; HNP-1; HP-1; HP1
• Gene Name: DEFA1
• Related Disease:
  Coronary atherosclerosis
  Coronary heart disease
  Type-1 diabetes
  Adenoma
  Alzheimer disease
  Alzheimer disease 3
  Behcet disease
  Breast cancer
  Chronic obstructive pulmonary disease
  Chronic pancreatitis
  Diabetic kidney disease
  Influenza
  Major depressive disorder
  Matthew-Wood syndrome
  Neoplasm
  Periodontal disease
  Renal cell carcinoma
  Adenovirus infection
  Adenocarcinoma
  Advanced cancer
  Bacterial vaginosis
  Crohn disease
  Non-insulin dependent diabetes
  Periodontitis
  Rheumatoid arthritis
  Type-1/2 diabetes
• UniProt ID: DEF1_HUMAN
• PDB ID: 2KHT; 2PM1; 3GNY; 3H6C; 3HJ2; 3HJD; 3LO1; 3LO2; 3LO4; 3LO6; 3LO9; 3LOE; 3LVX; 4DU0; 4LB1; 4LB7; 4LBB; 4LBF
• Pfam ID: PF00323 ; PF00879
• Sequence:
  MRTLAILAAILLVALQAQAEPLQARADEVAAAPEQIAADIPEVVVSLAWDESLAPKHPGS
  RKNMACYCRIPACIAGERRYGTCIYQGRLWAFCC
• Function: Effector molecule of the innate immune system that acts via antibiotic-like properties against a broad array of infectious agents including bacteria, fungi, and viruses or by promoting the activation and maturation of some APCs. Interacts with the essential precursor of cell wall synthesis lipid II to inhibit bacterial cell wall synthesis. Inhibits adenovirus infection via inhibition of viral disassembly at the vertex region, thereby restricting the release of internal capsid protein pVI, which is required for endosomal membrane penetration during cell entry. In addition, interaction with adenovirus capsid leads to the redirection of viral particles to TLR4 thereby promoting a NLRP3-mediated inflammasome response and interleukin 1-beta (IL-1beta) release. Induces the production of proinflammatory cytokines including type I interferon (IFN) in plasmacytoid dendritic cells (pDCs) by triggering the degradation of NFKBIA and nuclear translocation of IRF1, both of which are required for activation of pDCs.
• KEGG Pathway:
  NOD-like receptor sig.ling pathway (hsa04621)
  Staphylococcus aureus infection (hsa05150)
  Transcriptio.l misregulation in cancer (hsa05202)
• Reactome Pathway:
  Alpha-defensins (R-HSA-1462054)
  Neutrophil degranulation (R-HSA-6798695)
  Defensins (R-HSA-1461973)

Molecular Interaction Atlas (MIA) of This DOT

26 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Coronary atherosclerosis	DISKNDYU	Definitive	Biomarker	[1]
Coronary heart disease	DIS5OIP1	Definitive	Biomarker	[1]
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[2]
Adenoma	DIS78ZEV	Strong	Altered Expression	[3]
Alzheimer disease	DISF8S70	Strong	Altered Expression	[4]
Alzheimer disease 3	DISVT69G	Strong	Altered Expression	[4]
Behcet disease	DISSYMBS	Strong	Genetic Variation	[5]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[6]
Chronic obstructive pulmonary disease	DISQCIRF	Strong	Biomarker	[7]
Chronic pancreatitis	DISBUOMJ	Strong	Altered Expression	[8]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[9]
Influenza	DIS3PNU3	Strong	Biomarker	[10]
Major depressive disorder	DIS4CL3X	Strong	Biomarker	[11]
Matthew-Wood syndrome	DISA7HR7	Strong	Altered Expression	[8]
Neoplasm	DISZKGEW	Strong	Altered Expression	[12]
Periodontal disease	DISJQHVN	Strong	Biomarker	[13]
Renal cell carcinoma	DISQZ2X8	Strong	Biomarker	[14]
Adenovirus infection	DISUYSBZ	moderate	Altered Expression	[15]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[16]
Advanced cancer	DISAT1Z9	Limited	Biomarker	[16]
Bacterial vaginosis	DISK2MZ2	Limited	Altered Expression	[17]
Crohn disease	DIS2C5Q8	Limited	Biomarker	[18]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[19]
Periodontitis	DISI9JOI	Limited	Genetic Variation	[20]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[21]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[19]

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 Neutrophil defensin 1 (DEFA1).	[22]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the methylation of Neutrophil defensin 1 (DEFA1).	[27]

5 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 Neutrophil defensin 1 (DEFA1).	[23]
Arsenic trioxide	DM61TA4	Approved	Arsenic trioxide increases the expression of Neutrophil defensin 1 (DEFA1).	[24]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Neutrophil defensin 1 (DEFA1).	[25]
Irinotecan	DMP6SC2	Approved	Irinotecan decreases the expression of Neutrophil defensin 1 (DEFA1).	[26]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Neutrophil defensin 1 (DEFA1).	[25]

References

• [1] PPBP and DEFA1/DEFA3 genes in hyperlipidaemia as feasible synergistic inflammatory biomarkers for coronary heart disease.Lipids Health Dis. 2017 Apr 19;16(1):80. doi: 10.1186/s12944-017-0471-0.
• [2] Characterization of host defense molecules in the human pancreas.Islets. 2019;11(4):89-101. doi: 10.1080/19382014.2019.1585165. Epub 2019 Jun 26.
• [3] Human Neutrophil Peptides 1-3--early markers in development of colorectal adenomas and carcinomas.Dis Markers. 2008;25(2):123-9. doi: 10.1155/2008/693937.
• [4] Relevance of defensin -2 and defensins (HNP1-3) in Alzheimer's disease.Psychiatry Res. 2016 May 30;239:342-5. doi: 10.1016/j.psychres.2016.03.045. Epub 2016 Mar 31.
• [5] Correlation of DEFA1 gene copy number variation with intestinal involvement in Behcet's disease.J Korean Med Sci. 2012 Jan;27(1):107-9. doi: 10.3346/jkms.2012.27.1.107. Epub 2011 Dec 19.
• [6] The EGFR-GEP100-Arf6-AMAP1 signaling pathway specific to breast cancer invasion and metastasis.Traffic. 2009 Aug;10(8):982-93. doi: 10.1111/j.1600-0854.2009.00917.x. Epub 2009 Apr 21.
• [7] Krppel-like zinc finger proteins in end-stage COPD lungs with and without severe alpha1-antitrypsin deficiency.Orphanet J Rare Dis. 2012 May 23;7:29. doi: 10.1186/1750-1172-7-29.
• [8] Antimicrobial Peptide Human Neutrophil Peptide 1 as a Potential Link Between Chronic Inflammation and Ductal Adenocarcinoma of the Pancreas.Pancreas. 2018 May/Jun;47(5):561-567. doi: 10.1097/MPA.0000000000001054.
• [9] Increased levels of alpha-defensin (-1, -2 and -3) in type 1 diabetic patients with nephropathy.Nephrol Dial Transplant. 2008 Mar;23(3):914-8. doi: 10.1093/ndt/gfm711. Epub 2007 Nov 14.
• [10] alpha-Defensin inhibits influenza virus replication by cell-mediated mechanism(s).J Infect Dis. 2007 Sep 15;196(6):835-43. doi: 10.1086/521027. Epub 2007 Aug 10.
• [11] Haptoglobin phenotypes and gene frequencies in unipolar major depression.Am J Psychiatry. 1994 Jan;151(1):112-6. doi: 10.1176/ajp.151.1.112.
• [12] Oncogenic relevant defensins: expression pattern and proliferation characteristics of human tumor cell lines.Tumour Biol. 2016 Jun;37(6):7959-66. doi: 10.1007/s13277-015-4701-7. Epub 2015 Dec 28.
• [13] The Human Salivary Antimicrobial Peptide Profile according to the Oral Microbiota in Health, Periodontitis and Smoking.J Innate Immun. 2019;11(5):432-444. doi: 10.1159/000494146. Epub 2018 Nov 28.
• [14] Human alpha-defensins HNPs-1, -2, and -3 in renal cell carcinoma: influences on tumor cell proliferation.Am J Pathol. 2002 Apr;160(4):1311-24. doi: 10.1016/s0002-9440(10)62558-8.
• [15] Human Neutrophil Defensin-1, -3, and -4 Are Elevated in Nasal Aspirates from Children with Naturally Occurring Adenovirus Infection.Can Respir J. 2018 Jul 31;2018:1038593. doi: 10.1155/2018/1038593. eCollection 2018.
• [16] Human -defensin (DEFA) gene expression helps to characterise benign and malignant salivary gland tumours.BMC Cancer. 2012 Oct 11;12:465. doi: 10.1186/1471-2407-12-465.
• [17] Midpregnancy vaginal fluid defensins, bacterial vaginosis, and risk of preterm delivery.Obstet Gynecol. 2008 Sep;112(3):524-31. doi: 10.1097/AOG.0b013e318184209b.
• [18] Alpha-defensins (-Defs) in Crohn's disease: decrease of ileal -Def 5 via permanent methylation and increase in plasma -Def 1-3 concentrations offering biomarker utility.Clin Exp Immunol. 2018 Apr;192(1):120-128. doi: 10.1111/cei.13085. Epub 2018 Jan 10.
• [19] Relevance of -defensins (HNP1-3) and defensin -1 in diabetes.World J Gastroenterol. 2014 Jul 21;20(27):9128-37. doi: 10.3748/wjg.v20.i27.9128.
• [20] A genome-wide association study identifies nucleotide variants at SIGLEC5 and DEFA1A3 as risk loci for periodontitis.Hum Mol Genet. 2017 Jul 1;26(13):2577-2588. doi: 10.1093/hmg/ddx151.
• [21] Intraarticular release and accumulation of defensins and bactericidal/permeability-increasing protein in patients with rheumatoid arthritis.J Rheumatol. 2003 Aug;30(8):1719-24.
• [22] 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.
• [23] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [24] Role of NADPH oxidase in arsenic-induced reactive oxygen species formation and cytotoxicity in myeloid leukemia cells. Proc Natl Acad Sci U S A. 2004 Mar 30;101(13):4578-83.
• [25] Expression and modulation of progesterone induced blocking factor (PIBF) and innate immune factors in human leukemia cell lines by progesterone and mifepristone. Leuk Lymphoma. 2007 Aug;48(8):1610-7. doi: 10.1080/10428190701471999.
• [26] In vitro and in vivo irinotecan-induced changes in expression profiles of cell cycle and apoptosis-associated genes in acute myeloid leukemia cells. Mol Cancer Ther. 2005 Jun;4(6):885-900.
• [27] 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.