Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTD4OOFK)

• DOT Name: Interferon alpha/beta receptor 1 (IFNAR1)
• Synonyms: IFN-R-1; IFN-alpha/beta receptor 1; Cytokine receptor class-II member 1; Cytokine receptor family 2 member 1; CRF2-1; Type I interferon receptor 1
• Gene Name: IFNAR1
• Related Disease: Immunodeficiency 106, susceptibility to viral infections
• UniProt ID: INAR1_HUMAN
• PDB ID: 3S98; 3SE3; 3SE4; 4PO6
• Pfam ID: PF09294 ; PF01108
• Sequence:
  MMVVLLGATTLVLVAVAPWVLSAAAGGKNLKSPQKVEVDIIDDNFILRWNRSDESVGNVT
  FSFDYQKTGMDNWIKLSGCQNITSTKCNFSSLKLNVYEEIKLRIRAEKENTSSWYEVDSF
  TPFRKAQIGPPEVHLEAEDKAIVIHISPGTKDSVMWALDGLSFTYSLVIWKNSSGVEERI
  ENIYSRHKIYKLSPETTYCLKVKAALLTSWKIGVYSPVHCIKTTVENELPPPENIEVSVQ
  NQNYVLKWDYTYANMTFQVQWLHAFLKRNPGNHLYKWKQIPDCENVKTTQCVFPQNVFQK
  GIYLLRVQASDGNNTSFWSEEIKFDTEIQAFLLPPVFNIRSLSDSFHIYIGAPKQSGNTP
  VIQDYPLIYEIIFWENTSNAERKIIEKKTDVTVPNLKPLTVYCVKARAHTMDEKLNKSSV
  FSDAVCEKTKPGNTSKIWLIVGICIALFALPFVIYAAKVFLRCINYVFFPSLKPSSSIDE
  YFSEQPLKNLLLSTSEEQIEKCFIIENISTIATVEETNQTDEDHKKYSSQTSQDSGNYSN
  EDESESKTSEELQQDFV
• Function: Together with IFNAR2, forms the heterodimeric receptor for type I interferons (including interferons alpha, beta, epsilon, omega and kappa). Type I interferon binding activates the JAK-STAT signaling cascade, resulting in transcriptional activation or repression of interferon-regulated genes that encode the effectors of the interferon response. Mechanistically, type I interferon-binding brings the IFNAR1 and IFNAR2 subunits into close proximity with one another, driving their associated Janus kinases (JAKs) (TYK2 bound to IFNAR1 and JAK1 bound to IFNAR2) to cross-phosphorylate one another. The activated kinases phosphorylate specific tyrosine residues on the intracellular domains of IFNAR1 and IFNAR2, forming docking sites for the STAT transcription factors. STAT proteins are then phosphorylated by the JAKs, promoting their translocation into the nucleus to regulate expression of interferon-regulated genes. Can also act independently of IFNAR2: form an active IFNB1 receptor by itself and activate a signaling cascade that does not involve activation of the JAK-STAT pathway.
• Tissue Specificity: IFN receptors are present in all tissues and even on the surface of most IFN-resistant cells. Isoform 1, isoform 2 and isoform 3 are expressed in the IFN-alpha sensitive myeloma cell line U266B1. Isoform 2 and isoform 3 are expressed in the IFN-alpha resistant myeloma cell line U266R. Isoform 1 is not expressed in IFN-alpha resistant myeloma cell line U266R.
• KEGG Pathway:
  Cytokine-cytokine receptor interaction (hsa04060)
  PI3K-Akt sig.ling pathway (hsa04151)
  Necroptosis (hsa04217)
  Osteoclast differentiation (hsa04380)
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  JAK-STAT sig.ling pathway (hsa04630)
  .tural killer cell mediated cytotoxicity (hsa04650)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
  Pathways in cancer (hsa05200)
• Reactome Pathway:
  Regulation of IFNA/IFNB signaling (R-HSA-912694)
  Potential therapeutics for SARS (R-HSA-9679191)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  Interferon alpha/beta signaling (R-HSA-909733)

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Immunodeficiency 106, susceptibility to viral infections	DISOJEXZ	Strong	Autosomal recessive	[1]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate increases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[6]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[7]
Fluorouracil	DMUM7HZ	Approved	Fluorouracil increases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[8]
Nicotine	DMWX5CO	Approved	Nicotine decreases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[9]
Amantadine	DMS3YE9	Approved	Amantadine affects the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[10]
Genistein	DM0JETC	Phase 2/3	Genistein decreases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[11]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[9]
Glyphosate	DM0AFY7	Investigative	Glyphosate decreases the expression of Interferon alpha/beta receptor 1 (IFNAR1).	[12]

References

• [1] Type I interferon limits influenza virus-induced acute lung injury by regulation of excessive inflammation in mice. Antiviral Res. 2013 Sep;99(3):230-7. doi: 10.1016/j.antiviral.2013.05.007. Epub 2013 May 28.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] Transcriptional and Metabolic Dissection of ATRA-Induced Granulocytic Differentiation in NB4 Acute Promyelocytic Leukemia Cells. Cells. 2020 Nov 5;9(11):2423. doi: 10.3390/cells9112423.
• [5] 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.
• [6] Bringing in vitro analysis closer to in vivo: studying doxorubicin toxicity and associated mechanisms in 3D human microtissues with PBPK-based dose modelling. Toxicol Lett. 2018 Sep 15;294:184-192.
• [7] 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.
• [8] The up-regulation of type I interferon receptor gene plays a key role in hepatocellular carcinoma cells in the synergistic antiproliferative effect by 5-fluorouracil and interferon-alpha. Int J Oncol. 2006 Dec;29(6):1469-78.
• [9] Effects of tobacco compounds on gene expression in fetal lung fibroblasts. Environ Toxicol. 2008 Aug;23(4):423-34.
• [10] Interferon signal transduction of biphenyl dimethyl dicarboxylate/amantadine and anti-HBV activity in HepG2 2.2.15. Arch Pharm Res. 2006 May;29(5):405-11. doi: 10.1007/BF02968591.
• [11] A high concentration of genistein down-regulates activin A, Smad3 and other TGF-beta pathway genes in human uterine leiomyoma cells. Exp Mol Med. 2012 Apr 30;44(4):281-92.
• [12] Glyphosate-based herbicides at low doses affect canonical pathways in estrogen positive and negative breast cancer cell lines. PLoS One. 2019 Jul 11;14(7):e0219610. doi: 10.1371/journal.pone.0219610. eCollection 2019.