Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT184CRZ)

• DOT Name: Hepatitis A virus cellular receptor 1 (HAVCR1)
• Synonyms: HAVcr-1; Kidney injury molecule 1; KIM-1; T-cell immunoglobulin and mucin domain-containing protein 1; TIMD-1; T-cell immunoglobulin mucin receptor 1; TIM; TIM-1; T-cell membrane protein 1; CD antigen CD365
• Gene Name: HAVCR1
• Related Disease:
  Allergic rhinitis
  Clear cell renal carcinoma
  Ebola virus infection
  Immune system disorder
  Allergic asthma
  Autism spectrum disorder
  Autoimmune disease
  Cervical Intraepithelial neoplasia
  Colorectal carcinoma
  Cystic fibrosis
  IgA nephropathy
  Lung cancer
  Lupus nephritis
  Nephropathy
  Non-insulin dependent diabetes
  Pneumonia
  Pneumonitis
  Rheumatoid arthritis
  Type-1 diabetes
  Type-1/2 diabetes
  Vascular purpura
  Cardiac failure
  Colitis
  Congestive heart failure
  Hepatitis A virus infection
  Kidney cancer
  Renal carcinoma
  Acute kidney injury
  Atopic dermatitis
  Breast cancer
  Breast carcinoma
  Cardiovascular disease
  Common variable immunodeficiency
  Dengue
  Diabetic kidney disease
  Focal segmental glomerulosclerosis
  Kidney neoplasm
  Lung carcinoma
  Myocardial infarction
  Renal cell carcinoma
  Renal tubule disorder
• UniProt ID: HAVR1_HUMAN
• PDB ID: 5DZO; 5F70
• Pfam ID: PF07686
• Sequence:
  MHPQVVILSLILHLADSVAGSVKVGGEAGPSVTLPCHYSGAVTSMCWNRGSCSLFTCQNG
  IVWTNGTHVTYRKDTRYKLLGDLSRRDVSLTIENTAVSDSGVYCCRVEHRGWFNDMKITV
  SLEIVPPKVTTTPIVTTVPTVTTVRTSTTVPTTTTVPMTTVPTTTVPTTMSIPTTTTVLT
  TMTVSTTTSVPTTTSIPTTTSVPVTTTVSTFVPPMPLPRQNHEPVATSPSSPQPAETHPT
  TLQGAIRREPTSSPLYSYTTDGNDTVTESSDGLWNNNQTQLFLEHSLLTANTTKGIYAGV
  CISVLVLLALLGVIIAKKYFFKKEVQQLSVSFSSLQIKALQNAVEKEVQAEDNIYIENSL
  YATD
• Function: Phosphatidylserine receptor that plays an important functional role in regulatory B-cells homeostasis including generation, expansion and suppressor functions. As P-selectin/SELPLG ligand, plays a specialized role in activated but not naive T-cell trafficking during inflammatory responses. Controls thereby T-cell accumulation in the inflamed central nervous system (CNS) and the induction of autoimmune disease. Regulates also expression of various anti-inflammatory cytokines and co-inhibitory ligands including IL10. Acts as a regulator of T-cell proliferation. May play a role in kidney injury and repair ; (Microbial infection) Acts as a receptor for Hepatitis A virus; (Microbial infection) Acts as a receptor for Ebolavirus and Marburg virus by binding exposed phosphatidyl-serine at the surface of virion membrane. Serves as a dual receptor for Ebolavirus by also interacting with envelope glycoprotein GP ; (Microbial infection) Acts as a receptor for Dengue virus by binding exposed phosphatidyl-serine at the surface of virion membrane. TIM1 and Dengue virus are co-internalized during virus entry ; (Microbial infection) Acts as a receptor for Zika virus by binding to envelope protein E; (Microbial infection) Plays a positive role in Chikungunya virus cell entry.
• Tissue Specificity: Widely expressed, with highest levels in kidney and testis. Expressed by activated CD4+ T-cells during the development of helper T-cells responses.
• KEGG Pathway:
  Virion - Flavivirus (hsa03264)
  Efferocytosis (hsa04148)
• Reactome Pathway: Attachment and Entry (R-HSA-9694614)

Molecular Interaction Atlas (MIA) of This DOT

41 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Allergic rhinitis	DIS3U9HN	Definitive	Biomarker	[1]
Clear cell renal carcinoma	DISBXRFJ	Definitive	Biomarker	[2]
Ebola virus infection	DISJAVM1	Definitive	Biomarker	[3]
Immune system disorder	DISAEGPH	Definitive	Biomarker	[4]
Allergic asthma	DISHF0H3	Strong	Genetic Variation	[5]
Autism spectrum disorder	DISXK8NV	Strong	Genetic Variation	[6]
Autoimmune disease	DISORMTM	Strong	Genetic Variation	[7]
Cervical Intraepithelial neoplasia	DISXP757	Strong	Altered Expression	[8]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[9]
Cystic fibrosis	DIS2OK1Q	Strong	Biomarker	[10]
IgA nephropathy	DISZ8MTK	Strong	Biomarker	[11]
Lung cancer	DISCM4YA	Strong	Altered Expression	[12]
Lupus nephritis	DISCVGPZ	Strong	Biomarker	[13]
Nephropathy	DISXWP4P	Strong	Biomarker	[4]
Non-insulin dependent diabetes	DISK1O5Z	Strong	Biomarker	[14]
Pneumonia	DIS8EF3M	Strong	Biomarker	[15]
Pneumonitis	DIS88E0K	Strong	Biomarker	[15]
Rheumatoid arthritis	DISTSB4J	Strong	Genetic Variation	[16]
Type-1 diabetes	DIS7HLUB	Strong	Biomarker	[17]
Type-1/2 diabetes	DISIUHAP	Strong	Altered Expression	[18]
Vascular purpura	DIS6ZZMF	Strong	Altered Expression	[19]
Cardiac failure	DISDC067	moderate	Biomarker	[20]
Colitis	DISAF7DD	moderate	Biomarker	[21]
Congestive heart failure	DIS32MEA	moderate	Biomarker	[20]
Hepatitis A virus infection	DISUMFQV	moderate	Biomarker	[4]
Kidney cancer	DISBIPKM	moderate	Biomarker	[22]
Renal carcinoma	DISER9XT	moderate	Biomarker	[22]
Acute kidney injury	DISXZG0T	Disputed	Biomarker	[23]
Atopic dermatitis	DISTCP41	Limited	Genetic Variation	[24]
Breast cancer	DIS7DPX1	Limited	Altered Expression	[25]
Breast carcinoma	DIS2UE88	Limited	Altered Expression	[25]
Cardiovascular disease	DIS2IQDX	Limited	Biomarker	[26]
Common variable immunodeficiency	DISHE7JQ	Limited	Genetic Variation	[27]
Dengue	DISKH221	Limited	Biomarker	[28]
Diabetic kidney disease	DISJMWEY	Limited	Biomarker	[18]
Focal segmental glomerulosclerosis	DISJNHH0	Limited	Biomarker	[29]
Kidney neoplasm	DISBNZTN	Limited	Biomarker	[30]
Lung carcinoma	DISTR26C	Limited	Altered Expression	[12]
Myocardial infarction	DIS655KI	Limited	Altered Expression	[31]
Renal cell carcinoma	DISQZ2X8	Limited	Biomarker	[2]
Renal tubule disorder	DISAFXMQ	Limited	Biomarker	[32]

18 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 Hepatitis A virus cellular receptor 1 (HAVCR1).	[33]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[34]
Arsenic	DMTL2Y1	Approved	Arsenic increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[35]
Hydrogen peroxide	DM1NG5W	Approved	Hydrogen peroxide affects the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[36]
Zoledronate	DMIXC7G	Approved	Zoledronate increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[37]
Menadione	DMSJDTY	Approved	Menadione affects the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[36]
Diclofenac	DMPIHLS	Approved	Diclofenac increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[38]
Gentamicin	DMKINJO	Approved	Gentamicin increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[40]
Polyethylene glycol	DM4I1JP	Approved	Polyethylene glycol increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[41]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[42]
Phenol	DM1QSM3	Phase 2/3	Phenol increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[41]
OTX-015	DMI8RG1	Phase 1/2	OTX-015 decreases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[43]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[44]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[43]
Mivebresib	DMCPF90	Phase 1	Mivebresib decreases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[43]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[41]
3R14S-OCHRATOXIN A	DM2KEW6	Investigative	3R14S-OCHRATOXIN A increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[45]
Paraquat	DMR8O3X	Investigative	Paraquat increases the expression of Hepatitis A virus cellular receptor 1 (HAVCR1).	[46]

3 Drug(s) Affected the Protein Interaction/Cellular Processes of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Cidofovir	DMA13GD	Approved	Cidofovir increases the secretion of Hepatitis A virus cellular receptor 1 (HAVCR1).	[39]
Oleic acid	DM54O1Z	Investigative	Oleic acid increases the secretion of Hepatitis A virus cellular receptor 1 (HAVCR1).	[47]
Linoleic acid	DMDGPY9	Investigative	Linoleic acid increases the secretion of Hepatitis A virus cellular receptor 1 (HAVCR1).	[47]

References

• [1] The T-cell immunoglobulin and mucin domain (Tim) gene family in asthma, allergy, and autoimmunity.Allergy Asthma Proc. 2013 Jan-Feb;34(1):e21-6. doi: 10.2500/aap.2013.34.3646.
• [2] Diagnostic role of kidney injury molecule-1 in renal cell carcinoma.Int Urol Nephrol. 2019 Nov;51(11):1893-1902. doi: 10.1007/s11255-019-02231-0. Epub 2019 Aug 5.
• [3] Biomechanical characterization of TIM protein-mediated Ebola virus-host cell adhesion.Sci Rep. 2019 Jan 22;9(1):267. doi: 10.1038/s41598-018-36449-2.
• [4] Understanding kidney injury molecule 1: a novel immune factor in kidney pathophysiology.Am J Transl Res. 2019 Mar 15;11(3):1219-1229. eCollection 2019.
• [5] Association analysis of -416G>C polymorphism of T-cell immunoglobulin and mucin domain-1 gene with asthma in Iran.Int J Immunogenet. 2015 Aug;42(4):265-9. doi: 10.1111/iji.12209. Epub 2015 Jun 3.
• [6] Dysregulation of T cell immunoglobulin and mucin domain 3 (TIM-3) signaling in peripheral immune cells is associated with immune dysfunction in autistic children.Mol Immunol. 2019 Feb;106:77-86. doi: 10.1016/j.molimm.2018.12.020. Epub 2018 Dec 24.
• [7] Association between T-Cell Immunoglobulin and Mucin Domain 3 (TIM-3) Genetic Polymorphisms and Susceptibility to Autoimmune Diseases.Immunol Invest. 2019 Aug;48(6):563-576. doi: 10.1080/08820139.2019.1599009. Epub 2019 May 2.
• [8] Evaluation of a Diagnostic Test of Serum Neutrophil Gelatinase-Associated Lipocalin (NGAL) and Urine KIM-1 in Contrast-Induced Nephropathy (CIN).Med Sci Monit. 2019 Jan 19;25:565-570. doi: 10.12659/MSM.912569.
• [9] HAVcR-1 expression in human colorectal cancer and its effects on colorectal cancer cells in vitro.Anticancer Res. 2013 Jan;33(1):207-14.
• [10] Urinary Biomarkers of Aminoglycoside-Induced Nephrotoxicity in Cystic Fibrosis: Kidney Injury Molecule-1 and Neutrophil Gelatinase-Associated Lipocalin.Sci Rep. 2018 Mar 23;8(1):5094. doi: 10.1038/s41598-018-23466-4.
• [11] Urinary Matrix Metalloproteinase 7 and Prediction of IgA Nephropathy Progression.Am J Kidney Dis. 2020 Mar;75(3):384-393. doi: 10.1053/j.ajkd.2019.07.018. Epub 2019 Oct 9.
• [12] Prognostic value of TIM-1 expression in human non-small-cell lung cancer.J Transl Med. 2019 May 28;17(1):178. doi: 10.1186/s12967-019-1931-2.
• [13] Composite urinary biomarkers to predict pathological tubulointerstitial lesions in lupus nephritis.Lupus. 2018 Oct;27(11):1778-1789. doi: 10.1177/0961203318788167. Epub 2018 Jul 18.
• [14] Serum kidney injury molecule 1 and (2)-microglobulin perform as well as larger biomarker panels for prediction of rapid decline in renal function in type 2 diabetes.Diabetologia. 2019 Jan;62(1):156-168. doi: 10.1007/s00125-018-4741-9. Epub 2018 Oct 5.
• [15] Tim1 and Tim3 are not essential for experimental allergic asthma.Clin Exp Allergy. 2011 Jul;41(7):1012-21. doi: 10.1111/j.1365-2222.2011.03728.x. Epub 2011 Apr 7.
• [16] TIM family gene polymorphism and susceptibility to rheumatoid arthritis: Systematic review and meta-analysis.PLoS One. 2019 Feb 7;14(2):e0211146. doi: 10.1371/journal.pone.0211146. eCollection 2019.
• [17] Protective effects of curcumin on diabetic nephropathy via attenuation of kidney injury molecule 1 (KIM-1) and neutrophil gelatinase-associated lipocalin (NGAL) expression and alleviation of oxidative stress in rats with type 1 diabetes.Iran J Basic Med Sci. 2019 Apr;22(4):376-383. doi: 10.22038/ijbms.2019.31922.7674.
• [18] Circulating kidney injury molecule-1 as a biomarker of renal parameters in diabetic kidney disease.J Diabetes Investig. 2020 Mar;11(2):435-440. doi: 10.1111/jdi.13139. Epub 2019 Sep 21.
• [19] Kidney Injury Molecule-1 Level is Associated with the Severity of Renal Interstitial Injury and Prognosis in Adult Henoch-Schnlein Purpura Nephritis.Arch Med Res. 2017 Jul;48(5):449-458. doi: 10.1016/j.arcmed.2017.10.005. Epub 2017 Nov 6.
• [20] Biomarker guidance allows a more personalized allocation of patients for remote patient management in heart failure: results from the TIM-HF2 trial.Eur J Heart Fail. 2019 Nov;21(11):1445-1458. doi: 10.1002/ejhf.1530. Epub 2019 Jun 17.
• [21] Early detection of renal injury using urinary vanin-1 in rats with experimental colitis.J Appl Toxicol. 2014 Feb;34(2):184-90. doi: 10.1002/jat.2849. Epub 2013 Jan 11.
• [22] KIM-1 as a Blood-Based Marker for Early Detection of Kidney Cancer: A Prospective Nested Case-Control Study.Clin Cancer Res. 2018 Nov 15;24(22):5594-5601. doi: 10.1158/1078-0432.CCR-18-1496. Epub 2018 Jul 23.
• [23] A Multiplatform Approach for the Discovery of Novel Drug-Induced Kidney Injury Biomarkers.Chem Res Toxicol. 2017 Oct 16;30(10):1823-1834. doi: 10.1021/acs.chemrestox.7b00159. Epub 2017 Sep 27.
• [24] Genetic association studies between the T cell immunoglobulin mucin (TIM) gene locus and childhood atopic dermatitis.Int Arch Allergy Immunol. 2006;141(4):331-6. doi: 10.1159/000095459. Epub 2006 Aug 29.
• [25] TIMELESS contributes to the progression of breast cancer through activation of MYC.Breast Cancer Res. 2017 May 2;19(1):53. doi: 10.1186/s13058-017-0838-1.
• [26] Blood kidney injury molecule-1 predicts short and longer term kidney outcomes in patients undergoing diagnostic coronary and/or peripheral angiography-Results from the Catheter Sampled Blood Archive in Cardiovascular Diseases (CASABLANCA) study.Am Heart J. 2019 Mar;209:36-46. doi: 10.1016/j.ahj.2018.12.001. Epub 2018 Dec 7.
• [27] Genome-wide association identifies diverse causes of common variable immunodeficiency.J Allergy Clin Immunol. 2011 Jun;127(6):1360-7.e6. doi: 10.1016/j.jaci.2011.02.039. Epub 2011 Apr 17.
• [28] TIM-1 As a Signal Receptor Triggers Dengue Virus-Induced Autophagy.Int J Mol Sci. 2019 Oct 2;20(19):4893. doi: 10.3390/ijms20194893.
• [29] Reduction of proteinuria in adriamycin-induced nephropathy is associated with reduction of renal kidney injury molecule (Kim-1) over time.Am J Physiol Renal Physiol. 2009 May;296(5):F1136-45. doi: 10.1152/ajprenal.00541.2007. Epub 2009 Feb 18.
• [30] A Phage Display-Identified Peptide Selectively Binds to Kidney Injury Molecule-1 (KIM-1) and Detects KIM-1-Overexpressing Tumors in vivo.Cancer Res Treat. 2019 Jul;51(3):861-875. doi: 10.4143/crt.2018.214. Epub 2018 Oct 1.
• [31] Canagliflozin, a sodium-glucose cotransporter2 inhibitor, normalizes renal susceptibility to type1 cardiorenal syndrome through reduction of renal oxidative stress in diabetic rats.J Diabetes Investig. 2019 Jul;10(4):933-946. doi: 10.1111/jdi.13009. Epub 2019 Feb 25.
• [32] Kidney injury molecule-1 expression predicts structural damage and outcome in histological acute tubular injury.Ren Fail. 2019 Nov;41(1):80-87. doi: 10.1080/0886022X.2019.1578234.
• [33] 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.
• [34] In vitro evaluation of biomarkers for cisplatin-induced nephrotoxicity using HK-2 human kidney epithelial cells. Toxicol Lett. 2013 Mar 13;217(3):235-42. doi: 10.1016/j.toxlet.2012.12.015. Epub 2012 Dec 31.
• [35] Inorganic arsenic exposure promotes malignant progression by HDAC6-mediated down-regulation of HTRA1. J Appl Toxicol. 2023 Aug;43(8):1214-1224. doi: 10.1002/jat.4457. Epub 2023 Mar 11.
• [36] Global gene expression analysis reveals differences in cellular responses to hydroxyl- and superoxide anion radical-induced oxidative stress in caco-2 cells. Toxicol Sci. 2010 Apr;114(2):193-203. doi: 10.1093/toxsci/kfp309. Epub 2009 Dec 31.
• [37] Zoledronate dysregulates fatty acid metabolism in renal tubular epithelial cells to induce nephrotoxicity. Arch Toxicol. 2018 Jan;92(1):469-485.
• [38] Urinary proteomic profiling reveals diclofenac-induced renal injury and hepatic regeneration in mice. Toxicol Appl Pharmacol. 2013 Jun 1;269(2):141-9. doi: 10.1016/j.taap.2013.03.005. Epub 2013 Mar 16.
• [39] Transporter-dependent cytotoxicity of antiviral drugs in primary cultures of human proximal tubular cells. Toxicology. 2018 Jul 1;404-405:10-24. doi: 10.1016/j.tox.2018.05.002. Epub 2018 May 5.
• [40] In vitro evaluation of biomarkers of nephrotoxicity through gene expression using gentamicin. J Biochem Mol Toxicol. 2018 Sep;32(9):e22189. doi: 10.1002/jbt.22189. Epub 2018 Jul 10.
• [41] Vanin-1: a potential biomarker for nephrotoxicant-induced renal injury. Toxicology. 2011 Nov 28;290(1):82-8. doi: 10.1016/j.tox.2011.08.019. Epub 2011 Sep 3.
• [42] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [43] 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.
• [44] 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.
• [45] Renal toxicity through AhR, PXR, and Nrf2 signaling pathway activation of ochratoxin A-induced oxidative stress in kidney cells. Food Chem Toxicol. 2018 Dec;122:59-68.
• [46] CD34+ derived macrophage and dendritic cells display differential responses to paraquat. Toxicol In Vitro. 2021 Sep;75:105198. doi: 10.1016/j.tiv.2021.105198. Epub 2021 Jun 9.
• [47] In vitro toxicological assessment of free 3-MCPD and select 3-MCPD esters on human proximal tubule HK-2 cells. Cell Biol Toxicol. 2020 Jun;36(3):209-221. doi: 10.1007/s10565-019-09498-0. Epub 2019 Nov 5.