Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT95CBQ9)

• DOT Name: Defensin alpha 5 (DEFA5)
• Synonyms: Defensin-5; HD5(20-94)
• Gene Name: DEFA5
• Related Disease:
  Acute graft versus host disease
  Bacillary dysentery
  Coeliac disease
  Colon cancer
  Colonic neoplasm
  Herpes simplex infection
  HIV infectious disease
  IgA nephropathy
  Inflammatory bowel disease
  Peutz-Jeghers syndrome
  Sexually transmitted infection
  Ulcerative colitis
  Bacterial infection
  Gastritis
  Meningioma
  Adenocarcinoma
  Adenoma
  Bacterial vaginosis
  Polyp
• UniProt ID: DEF5_HUMAN
• PDB ID: 1ZMP; 2LXZ; 2MIT; 3I5W; 4E82; 4E83; 4E86; 4RBW; 4RBX; 5CUI; 5CUJ; 5CUM
• Pfam ID: PF00323 ; PF00879
• Sequence:
  MRTIAILAAILLVALQAQAESLQERADEATTQKQSGEDNQDLAISFAGNGLSALRTSGSQ
  ARATCYCRTGRCATRESLSGVCEISGRLYRLCCR
• Function: Host-defense peptide that maintains sterility in the urogenital system. Has antimicrobial activity against a wide range of bacteria, including Gram-negative E.coli, P.aeruginosa and S.typhimurium, and Gram-positive E.aerogenes, S.aureus, B.cereus, E.faecium and L.monocytogenes. Confers resistance to intestinal infection by S.typhimurium. Exhibits antimicrobial activity against enteric commensal bacteria such as B.adolescentis, L.acidophilus, B.breve, L.fermentum, B.longum and S.thermophilus. Binds to bacterial membranes and causes membrane disintegration. Induces the secretion of the chemokine IL-8 by intestinal epithelial cells. Binds to B.antracis lef/lethal factor, a major virulence factor from B.anthracis, and neutralizes its enzymatic activity ; (Microbial infection) Acts as a target for S.flexneri infection by binding to the bacterium, possibly via bacterial surface proteins, and thereby augmenting infectivity via enhanced bacterial adhesion and invasion of epithelial cells and tissues.
• Tissue Specificity: Expressed in the gastrointestinal, reproductive, and urinary tracts (at protein level) . Expressed in Paneth cells of the small intestine (at protein level) . Expressed throughout the urothelium of the lower urinary tract and in the collecting tubules of the kidney (at protein level) . Expressed in stratified squamous epithelial cells of the female genital tract epithelia, such as in vagina, ectocervix, endocervix, endometrium, and fallopian tube (at protein level) . Endometrial expression correlates with stages of the menstrual cycle: Expression is low during the early proliferative phase, increased during the mid- to late proliferative phase, peaks during the early secretory phase of the cycle, and decreases during the mid- to late secretory phase .
• 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

19 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Acute graft versus host disease	DIS8KLVM	Strong	Genetic Variation	[1]
Bacillary dysentery	DISFZHKN	Strong	Biomarker	[2]
Coeliac disease	DISIY60C	Strong	Altered Expression	[3]
Colon cancer	DISVC52G	Strong	Biomarker	[4]
Colonic neoplasm	DISSZ04P	Strong	Biomarker	[4]
Herpes simplex infection	DISL1SAV	Strong	Altered Expression	[5]
HIV infectious disease	DISO97HC	Strong	Biomarker	[6]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[7]
Inflammatory bowel disease	DISGN23E	Strong	Biomarker	[8]
Peutz-Jeghers syndrome	DISF27ZJ	Strong	Biomarker	[9]
Sexually transmitted infection	DISIVIAL	Strong	Biomarker	[6]
Ulcerative colitis	DIS8K27O	Strong	Biomarker	[8]
Bacterial infection	DIS5QJ9S	moderate	Biomarker	[10]
Gastritis	DIS8G07K	moderate	Biomarker	[11]
Meningioma	DISPT4TG	moderate	Genetic Variation	[12]
Adenocarcinoma	DIS3IHTY	Limited	Altered Expression	[13]
Adenoma	DIS78ZEV	Limited	Altered Expression	[13]
Bacterial vaginosis	DISK2MZ2	Limited	Biomarker	[14]
Polyp	DISRSLYF	Limited	Altered Expression	[13]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Defensin alpha 5 (DEFA5).	[15]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Defensin alpha 5 (DEFA5).	[16]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 decreases the expression of Defensin alpha 5 (DEFA5).	[17]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Defensin alpha 5 (DEFA5).	[18]

References

• [1] Recipient single nucleotide polymorphisms in Paneth cell antimicrobial peptide genes and acute graft-versus-host disease: analysis of BMT CTN-0201 and -0901 samples.Br J Haematol. 2018 Sep;182(6):887-894. doi: 10.1111/bjh.15492. Epub 2018 Jul 13.
• [2] Defens-IN! Human -Defensin 5 Acts as an Unwitting Double Agent to Promote Shigella Infection.Immunity. 2018 Jun 19;48(6):1070-1072. doi: 10.1016/j.immuni.2018.05.015.
• [3] Bifidobacterium infantis NLS Super Strain Reduces the Expression of -Defensin-5, a Marker of Innate Immunity, in the Mucosa of Active Celiac Disease Patients.J Clin Gastroenterol. 2017 Oct;51(9):814-817. doi: 10.1097/MCG.0000000000000687.
• [4] Differential labeling by monoclonal antibodies Adnab-9 and anti-alpha-defensin 5 based on the distribution and adenomatous tissue content of colonic polyps.Dig Dis Sci. 2005 Apr;50(4):708-13. doi: 10.1007/s10620-005-2561-5.
• [5] Enhancement of antiviral activity of human alpha-defensin 5 against herpes simplex virus 2 by arginine mutagenesis at adaptive evolution sites.J Virol. 2013 Mar;87(5):2835-45. doi: 10.1128/JVI.02209-12. Epub 2012 Dec 26.
• [6] Key Determinants of Human -Defensin 5 and 6 for Enhancement of HIV Infectivity.Viruses. 2017 Aug 29;9(9):244. doi: 10.3390/v9090244.
• [7] Discovery of new risk loci for IgA nephropathy implicates genes involved in immunity against intestinal pathogens.Nat Genet. 2014 Nov;46(11):1187-96. doi: 10.1038/ng.3118. Epub 2014 Oct 12.
• [8] Human alpha defensin 5 is a candidate biomarker to delineate inflammatory bowel disease.PLoS One. 2017 Aug 17;12(8):e0179710. doi: 10.1371/journal.pone.0179710. eCollection 2017.
• [9] An anti-adenoma antibody, Adnab-9, may reflect the risk for neoplastic progression in familial hamartomatous polyposis syndromes.Dig Dis Sci. 2008 Mar;53(3):723-9. doi: 10.1007/s10620-007-9947-5. Epub 2007 Oct 13.
• [10] Self-Assembling Myristoylated Human -Defensin 5 as a Next-Generation Nanobiotics Potentiates Therapeutic Efficacy in Bacterial Infection.ACS Nano. 2018 Jun 26;12(6):5284-5296. doi: 10.1021/acsnano.7b09109. Epub 2018 Jun 8.
• [11] Defensin-mRNA expression in the upper gastrointestinal tract is modulated in children with celiac disease and Helicobacter pylori-positive gastritis.J Pediatr Gastroenterol Nutr. 2010 Jun;50(6):596-600. doi: 10.1097/MPG.0b013e3181cd26cd.
• [12] Risk of meningioma and common variation in genes related to innate immunity.Cancer Epidemiol Biomarkers Prev. 2010 May;19(5):1356-61. doi: 10.1158/1055-9965.EPI-09-1151. Epub 2010 Apr 20.
• [13] Paneth cell differentiation in colonic epithelial neoplasms: evidence for the role of the Apc/beta-catenin/Tcf pathway.Hum Pathol. 2009 Jun;40(6):872-80. doi: 10.1016/j.humpath.2008.12.003. Epub 2009 Mar 9.
• [14] Human defensins and cytokines in vaginal lavage fluid of women with bacterial vaginosis.Int J Gynaecol Obstet. 2008 Oct;103(1):50-4. doi: 10.1016/j.ijgo.2008.05.020. Epub 2008 Jul 16.
• [15] Blood transcript immune signatures distinguish a subset of people with elevated serum ALT from others given acetaminophen. Clin Pharmacol Ther. 2016 Apr;99(4):432-41.
• [16] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [17] Definition of transcriptome-based indices for quantitative characterization of chemically disturbed stem cell development: introduction of the STOP-Toxukn and STOP-Toxukk tests. Arch Toxicol. 2017 Feb;91(2):839-864.
• [18] 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.