Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT81U8ME)

• DOT Name: Interferon regulatory factor 3 (IRF3)
• Synonyms: IRF-3
• Gene Name: IRF3
• UniProt ID: IRF3_HUMAN
• PDB ID: 1J2F; 1QWT; 1T2K; 1ZOQ; 2O61; 2O6G; 2PI0; 3A77; 3QU6; 5JEJ; 5JEK; 5JEL; 5JEM; 5JEO; 5JER; 6SIV; 6SJA; 7JFL
• Pfam ID: PF00605 ; PF10401
• Sequence:
  MGTPKPRILPWLVSQLDLGQLEGVAWVNKSRTRFRIPWKHGLRQDAQQEDFGIFQAWAEA
  TGAYVPGRDKPDLPTWKRNFRSALNRKEGLRLAEDRSKDPHDPHKIYEFVNSGVGDFSQP
  DTSPDTNGGGSTSDTQEDILDELLGNMVLAPLPDPGPPSLAVAPEPCPQPLRSPSLDNPT
  PFPNLGPSENPLKRLLVPGEEWEFEVTAFYRGRQVFQQTISCPEGLRLVGSEVGDRTLPG
  WPVTLPDPGMSLTDRGVMSYVRHVLSCLGGGLALWRAGQWLWAQRLGHCHTYWAVSEELL
  PNSGHGPDGEVPKDKEGGVFDLGPFIVDLITFTEGSGRSPRYALWFCVGESWPQDQPWTK
  RLVMVKVVPTCLRALVEMARVGGASSLENTVDLHISNSHPLSLTSDQYKAYLQDLVEGMD
  FQGPGES
• Function: Key transcriptional regulator of type I interferon (IFN)-dependent immune responses which plays a critical role in the innate immune response against DNA and RNA viruses. Regulates the transcription of type I IFN genes (IFN-alpha and IFN-beta) and IFN-stimulated genes (ISG) by binding to an interferon-stimulated response element (ISRE) in their promoters. Acts as a more potent activator of the IFN-beta (IFNB) gene than the IFN-alpha (IFNA) gene and plays a critical role in both the early and late phases of the IFNA/B gene induction. Found in an inactive form in the cytoplasm of uninfected cells and following viral infection, double-stranded RNA (dsRNA), or toll-like receptor (TLR) signaling, is phosphorylated by IKBKE and TBK1 kinases. This induces a conformational change, leading to its dimerization and nuclear localization and association with CREB binding protein (CREBBP) to form dsRNA-activated factor 1 (DRAF1), a complex which activates the transcription of the type I IFN and ISG genes. Can activate distinct gene expression programs in macrophages and can induce significant apoptosis in primary macrophages. In response to Sendai virus infection, is recruited by TOMM70:HSP90AA1 to mitochondrion and forms an apoptosis complex TOMM70:HSP90AA1:IRF3:BAX inducing apoptosis. Key transcription factor regulating the IFN response during SARS-CoV-2 infection.
• Tissue Specificity: Expressed constitutively in a variety of tissues.
• KEGG Pathway:
  Toll-like receptor sig.ling pathway (hsa04620)
  NOD-like receptor sig.ling pathway (hsa04621)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Cytosolic D.-sensing pathway (hsa04623)
  Alcoholic liver disease (hsa04936)
  Shigellosis (hsa05131)
  Pertussis (hsa05133)
  Yersinia infection (hsa05135)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Human cytomegalovirus infection (hsa05163)
  Influenza A (hsa05164)
  Human papillomavirus infection (hsa05165)
  Kaposi sarcoma-associated herpesvirus infection (hsa05167)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Human immunodeficiency virus 1 infection (hsa05170)
  Coro.virus disease - COVID-19 (hsa05171)
  Viral carcinogenesis (hsa05203)
  Lipid and atherosclerosis (hsa05417)
• Reactome Pathway:
  IRF3 mediated activation of type 1 IFN (R-HSA-1606341)
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)
  LRR FLII-interacting protein 1 (LRRFIP1) activates type I IFN production (R-HSA-3134973)
  Regulation of innate immune responses to cytosolic DNA (R-HSA-3134975)
  IRF3-mediated induction of type I IFN (R-HSA-3270619)
  Interferon gamma signaling (R-HSA-877300)
  TICAM1-dependent activation of IRF3/IRF7 (R-HSA-9013973)
  Interferon alpha/beta signaling (R-HSA-909733)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  Activation of IRF3, IRF7 mediated by TBK1, IKK (IKBKE) (R-HSA-936964)
  SARS-CoV-1 activates/modulates innate immune responses (R-HSA-9692916)
  SARS-CoV-2 activates/modulates innate and adaptive immune responses (R-HSA-9705671)
  ISG15 antiviral mechanism (R-HSA-1169408)

Molecular Interaction Atlas (MIA) of This DOT

4 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 Interferon regulatory factor 3 (IRF3).	[1]
Hydroxychloroquine	DMSIVND	Approved	Hydroxychloroquine increases the phosphorylation of Interferon regulatory factor 3 (IRF3).	[10]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene affects the methylation of Interferon regulatory factor 3 (IRF3).	[11]
Coumarin	DM0N8ZM	Investigative	Coumarin increases the phosphorylation of Interferon regulatory factor 3 (IRF3).	[13]

10 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 Interferon regulatory factor 3 (IRF3).	[2]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Interferon regulatory factor 3 (IRF3).	[3]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Interferon regulatory factor 3 (IRF3).	[4]
Quercetin	DM3NC4M	Approved	Quercetin increases the expression of Interferon regulatory factor 3 (IRF3).	[5]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Interferon regulatory factor 3 (IRF3).	[6]
Selenium	DM25CGV	Approved	Selenium increases the expression of Interferon regulatory factor 3 (IRF3).	[7]
Gemcitabine	DMSE3I7	Approved	Gemcitabine decreases the expression of Interferon regulatory factor 3 (IRF3).	[8]
Diphenylpyraline	DMW4X37	Approved	Diphenylpyraline increases the expression of Interferon regulatory factor 3 (IRF3).	[9]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Interferon regulatory factor 3 (IRF3).	[12]
Nickel chloride	DMI12Y8	Investigative	Nickel chloride decreases the expression of Interferon regulatory factor 3 (IRF3).	[14]

References

• [1] 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.
• [2] Phenotypic characterization of retinoic acid differentiated SH-SY5Y cells by transcriptional profiling. PLoS One. 2013 May 28;8(5):e63862.
• [3] 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.
• [4] Quantitative proteomics reveals a broad-spectrum antiviral property of ivermectin, benefiting for COVID-19 treatment. J Cell Physiol. 2021 Apr;236(4):2959-2975. doi: 10.1002/jcp.30055. Epub 2020 Sep 22.
• [5] 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.
• [6] THC exposure of human iPSC neurons impacts genes associated with neuropsychiatric disorders. Transl Psychiatry. 2018 Apr 25;8(1):89. doi: 10.1038/s41398-018-0137-3.
• [7] Selenium and vitamin E: cell type- and intervention-specific tissue effects in prostate cancer. J Natl Cancer Inst. 2009 Mar 4;101(5):306-20.
• [8] Gene expression profiling of breast cancer cells in response to gemcitabine: NF-kappaB pathway activation as a potential mechanism of resistance. Breast Cancer Res Treat. 2007 Apr;102(2):157-72.
• [9] Controlled diesel exhaust and allergen coexposure modulates microRNA and gene expression in humans: Effects on inflammatory lung markers. J Allergy Clin Immunol. 2016 Dec;138(6):1690-1700. doi: 10.1016/j.jaci.2016.02.038. Epub 2016 Apr 24.
• [10] Hydroxychloroquine-inhibited dengue virus is associated with host defense machinery. J Interferon Cytokine Res. 2015 Mar;35(3):143-56. doi: 10.1089/jir.2014.0038. Epub 2014 Oct 16.
• [11] Effect of aflatoxin B(1), benzo[a]pyrene, and methapyrilene on transcriptomic and epigenetic alterations in human liver HepaRG cells. Food Chem Toxicol. 2018 Nov;121:214-223. doi: 10.1016/j.fct.2018.08.034. Epub 2018 Aug 26.
• [12] Cell-based two-dimensional morphological assessment system to predict cancer drug-induced cardiotoxicity using human induced pluripotent stem cell-derived cardiomyocytes. Toxicol Appl Pharmacol. 2019 Nov 15;383:114761. doi: 10.1016/j.taap.2019.114761. Epub 2019 Sep 15.
• [13] Quantitative phosphoproteomics reveal cellular responses from caffeine, coumarin and quercetin in treated HepG2 cells. Toxicol Appl Pharmacol. 2022 Aug 15;449:116110. doi: 10.1016/j.taap.2022.116110. Epub 2022 Jun 7.
• [14] Nickel-induced down-regulation of Np63 and its role in the proliferation of keratinocytes. Toxicol Appl Pharmacol. 2011 Jun 15;253(3):235-43. doi: 10.1016/j.taap.2011.03.024. Epub 2011 Apr 3.