Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTYTSO77)

• DOT Name: Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5)
• Synonyms: IFIT-5; Interferon-induced 58 kDa protein; Retinoic acid- and interferon-inducible 58 kDa protein; P58
• Gene Name: IFIT5
• Related Disease:
  Neoplasm
  Breast cancer
  Breast carcinoma
  Hepatitis C virus infection
  Influenza
  Prostate cancer
  Prostate carcinoma
  Bladder cancer
  Urinary bladder cancer
  Urinary bladder neoplasm
• UniProt ID: IFIT5_HUMAN
• PDB ID: 3ZGQ; 4HOQ; 4HOR; 4HOS; 4HOT; 4J0U
• Pfam ID: PF13374 ; PF13424 ; PF07719 ; PF13181
• Sequence:
  MSEIRKDTLKAILLELECHFTWNLLKEDIDLFEVEDTIGQQLEFLTTKSRLALYNLLAYV
  KHLKGQNKDALECLEQAEEIIQQEHSDKEEVRSLVTWGNYAWVYYHMDQLEEAQKYTGKI
  GNVCKKLSSPSNYKLECPETDCEKGWALLKFGGKYYQKAKAAFEKALEVEPDNPEFNIGY
  AITVYRLDDSDREGSVKSFSLGPLRKAVTLNPDNSYIKVFLALKLQDVHAEAEGEKYIEE
  ILDQISSQPYVLRYAAKFYRRKNSWNKALELLKKALEVTPTSSFLHHQMGLCYRAQMIQI
  KKATHNRPKGKDKLKVDELISSAIFHFKAAMERDSMFAFAYTDLANMYAEGGQYSNAEDI
  FRKALRLENITDDHKHQIHYHYGRFQEFHRKSENTAIHHYLEALKVKDRSPLRTKLTSAL
  KKLSTKRLCHNALDVQSLSALGFVYKLEGEKRQAAEYYEKAQKIDPENAEFLTALCELRL
  SI
• Function: Interferon-induced RNA-binding protein involved in the human innate immune response. Has a broad and adaptable RNA structure recognition important for RNA recognition specificity in antiviral defense. Binds precursor and processed tRNAs as well as poly-U-tailed tRNA fragments. Specifically binds single-stranded RNA bearing a 5'-triphosphate group (PPP-RNA), thereby acting as a sensor of viral single-stranded RNAs. Single-stranded PPP-RNAs, which lack 2'-O-methylation of the 5' cap and bear a 5'-triphosphate group instead, are specific from viruses, providing a molecular signature to distinguish between self and non-self mRNAs by the host during viral infection. Directly binds PPP-RNA in a non-sequence-specific manner. Also recognizes and selectively binds AT-rich dsDNA. Additionally, as a mediator in innate immunity, positively regulates IKK-NFKB signaling by sinergizing the recruitment of IKK to MAP3K7.
• Reactome Pathway: Interferon alpha/beta signaling (R-HSA-909733)

Molecular Interaction Atlas (MIA) of This DOT

10 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Neoplasm	DISZKGEW	Definitive	Biomarker	[1]
Breast cancer	DIS7DPX1	Strong	Altered Expression	[2]
Breast carcinoma	DIS2UE88	Strong	Altered Expression	[2]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[3]
Influenza	DIS3PNU3	Strong	Biomarker	[4]
Prostate cancer	DISF190Y	Strong	Biomarker	[5]
Prostate carcinoma	DISMJPLE	Strong	Biomarker	[5]
Bladder cancer	DISUHNM0	moderate	Biomarker	[6]
Urinary bladder cancer	DISDV4T7	moderate	Biomarker	[6]
Urinary bladder neoplasm	DIS7HACE	moderate	Biomarker	[6]

13 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-induced protein with tetratricopeptide repeats 5 (IFIT5).	[7]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[8]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[9]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[10]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[11]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[12]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[13]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[14]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[15]
Hydroquinone	DM6AVR4	Approved	Hydroquinone decreases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[16]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[18]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Interferon-induced protein with tetratricopeptide repeats 5 (IFIT5).	[19]

References

• [1] IFN-Induced IFIT5 Promotes Epithelial-to-Mesenchymal Transition in Prostate Cancer via miRNA Processing.Cancer Res. 2019 Mar 15;79(6):1098-1112. doi: 10.1158/0008-5472.CAN-18-2207. Epub 2018 Nov 30.
• [2] Increased susceptibility of breast cancer cells to stress mediated inhibition of protein synthesis.Cancer Res. 2008 Jun 15;68(12):4862-74. doi: 10.1158/0008-5472.CAN-08-0074.
• [3] Characterization of a Threonine-Rich Cluster in Hepatitis C Virus Nonstructural Protein 5A and Its Contribution to Hyperphosphorylation.J Virol. 2018 Nov 27;92(24):e00737-18. doi: 10.1128/JVI.00737-18. Print 2018 Dec 15.
• [4] Chickens Expressing IFIT5 Ameliorate Clinical Outcome and Pathology of Highly Pathogenic Avian Influenza and Velogenic Newcastle Disease Viruses.Front Immunol. 2018 Sep 14;9:2025. doi: 10.3389/fimmu.2018.02025. eCollection 2018.
• [5] IFN, a Double-Edged Sword in Cancer Immunity and Metastasis.Cancer Res. 2019 Mar 15;79(6):1032-1033. doi: 10.1158/0008-5472.CAN-19-0083.
• [6] The roles and mechanism of IFIT5 in bladder cancer epithelial-mesenchymal transition and progression.Cell Death Dis. 2019 Jun 4;10(6):437. doi: 10.1038/s41419-019-1669-z.
• [7] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [8] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [9] 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.
• [10] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [11] Long-term estrogen exposure promotes carcinogen bioactivation, induces persistent changes in gene expression, and enhances the tumorigenicity of MCF-7 human breast cancer cells. Toxicol Appl Pharmacol. 2009 Nov 1;240(3):355-66.
• [12] 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.
• [13] 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.
• [14] Temozolomide induces activation of Wnt/-catenin signaling in glioma cells via PI3K/Akt pathway: implications in glioma therapy. Cell Biol Toxicol. 2020 Jun;36(3):273-278. doi: 10.1007/s10565-019-09502-7. Epub 2019 Nov 22.
• [15] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [16] Keratinocyte-derived IL-36gama plays a role in hydroquinone-induced chemical leukoderma through inhibition of melanogenesis in human epidermal melanocytes. Arch Toxicol. 2019 Aug;93(8):2307-2320.
• [17] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [18] Gene expression changes associated with altered growth and differentiation in benzo[a]pyrene or arsenic exposed normal human epidermal keratinocytes. J Appl Toxicol. 2008 May;28(4):491-508.
• [19] From transient transcriptome responses to disturbed neurodevelopment: role of histone acetylation and methylation as epigenetic switch between reversible and irreversible drug effects. Arch Toxicol. 2014 Jul;88(7):1451-68.