Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTUOPIS5)

• DOT Name: Liver-expressed antimicrobial peptide 2 (LEAP2)
• Synonyms: LEAP-2
• Gene Name: LEAP2
• Related Disease:
  Type-1 diabetes
  Bacterial infection
  HIV infectious disease
  Metabolic disorder
  Polycystic ovarian syndrome
  Keratoconjunctivitis sicca
  Obesity
• UniProt ID: LEAP2_HUMAN
• PDB ID: 2L1Q
• Pfam ID: PF07359
• Sequence:
  MWHLKLCAVLMIFLLLLGQIDGSPIPEVSSAKRRPRRMTPFWRGVSLRPIGASCRDDSEC
  ITRLCRKRRCSLSVAQE
• Function: Has an antimicrobial activity.
• Reactome Pathway: Antimicrobial peptides (R-HSA-6803157)

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Type-1 diabetes	DIS7HLUB	Definitive	Biomarker	[1]
Bacterial infection	DIS5QJ9S	Strong	Altered Expression	[2]
HIV infectious disease	DISO97HC	Strong	Altered Expression	[3]
Metabolic disorder	DIS71G5H	Strong	Biomarker	[4]
Polycystic ovarian syndrome	DISZ2BNG	moderate	Altered Expression	[5]
Keratoconjunctivitis sicca	DISNOENH	Limited	Biomarker	[6]
Obesity	DIS47Y1K	Limited	Biomarker	[7]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[8]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[9]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[10]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[11]
Estradiol	DMUNTE3	Approved	Estradiol decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[12]
Rosiglitazone	DMILWZR	Approved	Rosiglitazone decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[13]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[14]
Clozapine	DMFC71L	Approved	Clozapine increases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[15]
Bosentan	DMIOGBU	Approved	Bosentan affects the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[17]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[18]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[9]
Leflunomide	DMR8ONJ	Phase 1 Trial	Leflunomide increases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[19]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[18]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A affects the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[20]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[21]
OXYQUINOLINE	DMZVS9Y	Investigative	OXYQUINOLINE decreases the expression of Liver-expressed antimicrobial peptide 2 (LEAP2).	[12]

References

• [1] LEAP2 changes with body mass and food intake in humans and mice.J Clin Invest. 2019 Sep 3;129(9):3909-3923. doi: 10.1172/JCI125332.
• [2] Porcine liver-expressed antimicrobial peptides, hepcidin and LEAP-2: cloning and induction by bacterial infection.Dev Comp Immunol. 2006;30(4):357-66. doi: 10.1016/j.dci.2005.06.004. Epub 2005 Jul 7.
• [3] Immune activation in HIV/HCV-infected patients is associated with low-level expression of liver expressed antimicrobial peptide-2 (LEAP-2).J Clin Pathol. 2013 Nov;66(11):967-75. doi: 10.1136/jclinpath-2013-201581. Epub 2013 Aug 12.
• [4] Ghrelin and LEAP-2: Rivals in Energy Metabolism.Trends Pharmacol Sci. 2018 Aug;39(8):685-694. doi: 10.1016/j.tips.2018.06.004. Epub 2018 Jun 29.
• [5] Decreased levels of liver-expressed antimicrobial peptide-2 and ghrelin are related to insulin resistance in women with polycystic ovary syndrome.Gynecol Endocrinol. 2020 Mar;36(3):222-225. doi: 10.1080/09513590.2019.1665646. Epub 2019 Sep 17.
• [6] Increased expression of hepcidin and toll-like receptors 8 and 10 in viral keratitis.Cornea. 2011 Aug;30(8):899-904. doi: 10.1097/ICO.0b013e31820126e5.
• [7] Plasma levels of ghrelin, des-acyl ghrelin and LEAP2 in children with obesity: correlation with age and insulin resistance.Eur J Endocrinol. 2020 Feb;182(2):165-175. doi: 10.1530/EJE-19-0684.
• [8] 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.
• [9] Comparison of HepG2 and HepaRG by whole-genome gene expression analysis for the purpose of chemical hazard identification. Toxicol Sci. 2010 May;115(1):66-79.
• [10] Gene expression analysis of precision-cut human liver slices indicates stable expression of ADME-Tox related genes. Toxicol Appl Pharmacol. 2011 May 15;253(1):57-69.
• [11] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [12] Comparison of phenotypic and transcriptomic effects of false-positive genotoxins, true genotoxins and non-genotoxins using HepG2 cells. Mutagenesis. 2011 Sep;26(5):593-604.
• [13] Transcriptomic analysis of untreated and drug-treated differentiated HepaRG cells over a 2-week period. Toxicol In Vitro. 2015 Dec 25;30(1 Pt A):27-35.
• [14] A transcriptomics-based in vitro assay for predicting chemical genotoxicity in vivo. Carcinogenesis. 2012 Jul;33(7):1421-9.
• [15] Histamine H4 receptor agonists have more activities than H4 agonism in antigen-specific human T-cell responses. Immunology. 2007 Jun;121(2):266-75. doi: 10.1111/j.1365-2567.2007.02574.x. Epub 2007 Mar 7.
• [16] Omics-based responses induced by bosentan in human hepatoma HepaRG cell cultures. Arch Toxicol. 2018 Jun;92(6):1939-1952.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Comprehensive transcriptome profiling of BET inhibitor-treated HepG2 cells. PLoS One. 2022 Apr 29;17(4):e0266966. doi: 10.1371/journal.pone.0266966. eCollection 2022.
• [19] Endoplasmic reticulum stress and MAPK signaling pathway activation underlie leflunomide-induced toxicity in HepG2 Cells. Toxicology. 2017 Dec 1;392:11-21.
• [20] Comprehensive analysis of transcriptomic changes induced by low and high doses of bisphenol A in HepG2 spheroids in vitro and rat liver in vivo. Environ Res. 2019 Jun;173:124-134. doi: 10.1016/j.envres.2019.03.035. Epub 2019 Mar 18.
• [21] Gene expression changes in primary human nasal epithelial cells exposed to formaldehyde in vitro. Toxicol Lett. 2010 Oct 5;198(2):289-95.