Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTO3N8E1)

• DOT Name: Neutrophil defensin 3 (DEFA3)
• Synonyms: Defensin, alpha 3; HNP-3; HP-3; HP3
• Gene Name: DEFA3
• Related Disease:
  Coronary atherosclerosis
  Coronary heart disease
  Hyperlipidemia
  Adenoma
  Diabetic kidney disease
  IgA nephropathy
  Neoplasm
  Promyelocytic leukaemia
  Systemic lupus erythematosus
  Bacterial vaginosis
  Non-insulin dependent diabetes
  Rheumatoid arthritis
  Type-1/2 diabetes
• UniProt ID: DEF3_HUMAN
• PDB ID: 1DFN; 1ZMH; 1ZMI; 1ZMK; 2PM4; 2PM5
• Pfam ID: PF00323 ; PF00879
• Sequence:
  MRTLAILAAILLVALQAQAEPLQARADEVAAAPEQIAADIPEVVVSLAWDESLAPKHPGS
  RKNMDCYCRIPACIAGERRYGTCIYQGRLWAFCC
• 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. Possesses the ability to neutralize bacterial toxins such as B. anthracis lethal factor, Clostridium difficile cytotoxin B as well as leukocidin produced by Staphylococcus aureus. Blocks also herpes simplex virus infection by interacting with envelope glycoprotein B and thus preventing its binding to heparan sulfate, the receptor for attachment.
• 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)
  Defensins (R-HSA-1461973)

Molecular Interaction Atlas (MIA) of This DOT

13 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]
Hyperlipidemia	DIS61J3S	Definitive	Biomarker	[1]
Adenoma	DIS78ZEV	Strong	Altered Expression	[2]
Diabetic kidney disease	DISJMWEY	Strong	Biomarker	[3]
IgA nephropathy	DISZ8MTK	Strong	Genetic Variation	[4]
Neoplasm	DISZKGEW	Strong	Altered Expression	[5]
Promyelocytic leukaemia	DISYGG13	Strong	Therapeutic	[6]
Systemic lupus erythematosus	DISI1SZ7	Strong	Altered Expression	[7]
Bacterial vaginosis	DISK2MZ2	Limited	Altered Expression	[8]
Non-insulin dependent diabetes	DISK1O5Z	Limited	Genetic Variation	[9]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[10]
Type-1/2 diabetes	DISIUHAP	Limited	Genetic Variation	[9]

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 3 (DEFA3).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Neutrophil defensin 3 (DEFA3).	[14]

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 Neutrophil defensin 3 (DEFA3).	[12]
Progesterone	DMUY35B	Approved	Progesterone increases the expression of Neutrophil defensin 3 (DEFA3).	[13]
Mifepristone	DMGZQEF	Approved	Mifepristone decreases the expression of Neutrophil defensin 3 (DEFA3).	[13]

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] 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.
• [3] 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.
• [4] Low -defensin gene copy number increases the risk for IgA nephropathy and renal dysfunction.Sci Transl Med. 2016 Jun 29;8(345):345ra88. doi: 10.1126/scitranslmed.aaf2106.
• [5] 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.
• [6] Assessment of the cellular response to the induced expression of defensin sense and antisense cDNA in acute promyelocytic leukemia cell lines.Leuk Lymphoma. 2005 May;46(5):743-52. doi: 10.1080/10428190500051018.
• [7] Interferon and granulopoiesis signatures in systemic lupus erythematosus blood.J Exp Med. 2003 Mar 17;197(6):711-23. doi: 10.1084/jem.20021553.
• [8] Midpregnancy vaginal fluid defensins, bacterial vaginosis, and risk of preterm delivery.Obstet Gynecol. 2008 Sep;112(3):524-31. doi: 10.1097/AOG.0b013e318184209b.
• [9] 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.
• [10] Intraarticular release and accumulation of defensins and bactericidal/permeability-increasing protein in patients with rheumatoid arthritis.J Rheumatol. 2003 Aug;30(8):1719-24.
• [11] 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.
• [12] Systems analysis of transcriptome and proteome in retinoic acid/arsenic trioxide-induced cell differentiation/apoptosis of promyelocytic leukemia. Proc Natl Acad Sci U S A. 2005 May 24;102(21):7653-8.
• [13] 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.
• [14] 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.