Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTCA9WCM)

• DOT Name: S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2)
• Synonyms: SAND; EC 4.2.-.-; Cytomegalovirus-induced gene 5 protein; Radical S-adenosyl methionine domain-containing protein 2; Virus inhibitory protein, endoplasmic reticulum-associated, interferon-inducible; Viperin
• Gene Name: RSAD2
• Related Disease:
  Arteriosclerosis
  Atherosclerosis
  Chikungunya virus infection
  Cytomegalovirus infection
  Dengue
  Epithelial ovarian cancer
  Hepatitis B virus infection
  Hepatitis C virus infection
  Influenza
  Metabolic disorder
  Myocardial ischemia
  Nephropathy
  Ovarian cancer
  Ovarian neoplasm
  Rabies
  Viral respiratory tract infection
  Zika virus infection
  Bacterial infection
  Chronic obstructive pulmonary disease
  Venous thromboembolism
  Asthma
  Enterovirus infection
  Eosinophilic esophagitis
  Neoplasm
  Neuroblastoma
• UniProt ID: RSAD2_HUMAN
• EC Number: 4.2.-.-
• Pfam ID: PF13353 ; PF04055
• Sequence:
  MWVLTPAAFAGKLLSVFRQPLSSLWRSLVPLFCWLRATFWLLATKRRKQQLVLRGPDETK
  EEEEDPPLPTTPTSVNYHFTRQCNYKCGFCFHTAKTSFVLPLEEAKRGLLLLKEAGMEKI
  NFSGGEPFLQDRGEYLGKLVRFCKVELRLPSVSIVSNGSLIRERWFQNYGEYLDILAISC
  DSFDEEVNVLIGRGQGKKNHVENLQKLRRWCRDYRVAFKINSVINRFNVEEDMTEQIKAL
  NPVRWKVFQCLLIEGENCGEDALREAERFVIGDEEFERFLERHKEVSCLVPESNQKMKDS
  YLILDEYMRFLNCRKGRKDPSKSILDVGVEEAIKFSGFDEKMFLKRGGKYIWSKADLKLD
  W
• Function: Interferon-inducible antiviral protein which plays a major role in the cell antiviral state induced by type I and type II interferon. Catalyzes the conversion of cytidine triphosphate (CTP) to 3'-deoxy-3',4'-didehydro-CTP (ddhCTP) via a SAM-dependent radical mechanism. In turn, ddhCTP acts as a chain terminator for the RNA-dependent RNA polymerases from multiple viruses and directly inhibits viral replication. Therefore, inhibits a wide range of DNA and RNA viruses, including human cytomegalovirus (HCMV), hepatitis C virus (HCV), west Nile virus (WNV), dengue virus, sindbis virus, influenza A virus, sendai virus, vesicular stomatitis virus (VSV), zika virus, and human immunodeficiency virus (HIV-1). Promotes also TLR7 and TLR9-dependent production of IFN-beta production in plasmacytoid dendritic cells (pDCs) by facilitating 'Lys-63'-linked ubiquitination of IRAK1 by TRAF6. Plays a role in CD4+ T-cells activation and differentiation. Facilitates T-cell receptor (TCR)-mediated GATA3 activation and optimal T-helper 2 (Th2) cytokine production by modulating NFKB1 and JUNB activities. Can inhibit secretion of soluble proteins.
• KEGG Pathway:
  Hepatitis C (hsa05160)
  Influenza A (hsa05164)
• Reactome Pathway: Interferon alpha/beta signaling (R-HSA-909733)

Molecular Interaction Atlas (MIA) of This DOT

25 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Arteriosclerosis	DISK5QGC	Strong	Biomarker	[1]
Atherosclerosis	DISMN9J3	Strong	Altered Expression	[1]
Chikungunya virus infection	DISDXEHY	Strong	Biomarker	[2]
Cytomegalovirus infection	DISCEMGC	Strong	Biomarker	[3]
Dengue	DISKH221	Strong	Biomarker	[4]
Epithelial ovarian cancer	DIS56MH2	Strong	Altered Expression	[5]
Hepatitis B virus infection	DISLQ2XY	Strong	Altered Expression	[6]
Hepatitis C virus infection	DISQ0M8R	Strong	Biomarker	[7]
Influenza	DIS3PNU3	Strong	Biomarker	[8]
Metabolic disorder	DIS71G5H	Strong	Altered Expression	[9]
Myocardial ischemia	DISFTVXF	Strong	Biomarker	[10]
Nephropathy	DISXWP4P	Strong	Biomarker	[11]
Ovarian cancer	DISZJHAP	Strong	Altered Expression	[5]
Ovarian neoplasm	DISEAFTY	Strong	Altered Expression	[5]
Rabies	DISSC4V5	Strong	Biomarker	[7]
Viral respiratory tract infection	DIS7KC5K	Strong	Biomarker	[12]
Zika virus infection	DISQUCTY	Strong	Altered Expression	[13]
Bacterial infection	DIS5QJ9S	moderate	Altered Expression	[14]
Chronic obstructive pulmonary disease	DISQCIRF	moderate	Altered Expression	[15]
Venous thromboembolism	DISUR7CR	moderate	Genetic Variation	[16]
Asthma	DISW9QNS	Limited	Biomarker	[17]
Enterovirus infection	DISH2UDP	Limited	Biomarker	[18]
Eosinophilic esophagitis	DISR8WSB	Limited	Altered Expression	[19]
Neoplasm	DISZKGEW	Limited	Altered Expression	[20]
Neuroblastoma	DISVZBI4	Limited	Biomarker	[18]

23 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 S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[21]
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[22]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[23]
Acetaminophen	DMUIE76	Approved	Acetaminophen increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[24]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[25]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[26]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[27]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[28]
Calcitriol	DM8ZVJ7	Approved	Calcitriol decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[29]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[30]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[30]
Testosterone enanthate	DMB6871	Approved	Testosterone enanthate affects the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[31]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[30]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[30]
Malathion	DMXZ84M	Approved	Malathion increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[32]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[30]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[30]
Tofacitinib	DMBS370	Approved	Tofacitinib decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[33]
Hydroxychloroquine	DMSIVND	Approved	Hydroxychloroquine increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[34]
Resveratrol	DM3RWXL	Phase 3	Resveratrol increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[35]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[36]
Formaldehyde	DM7Q6M0	Investigative	Formaldehyde decreases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[37]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of S-adenosylmethionine-dependent nucleotide dehydratase RSAD2 (RSAD2).	[38]

References

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• [2] Viperin restricts chikungunya virus replication and pathology.J Clin Invest. 2012 Dec;122(12):4447-60. doi: 10.1172/JCI63120. Epub 2012 Nov 19.
• [3] Viperin regulates cellular lipid metabolism during human cytomegalovirus infection.PLoS Pathog. 2013;9(8):e1003497. doi: 10.1371/journal.ppat.1003497. Epub 2013 Aug 1.
• [4] Dengue virus infects the mouse eye following systemic or intracranial infection and induces inflammatory responses.J Gen Virol. 2020 Jan;101(1):79-85. doi: 10.1099/jgv.0.001354.
• [5] A key anti-viral protein, RSAD2/VIPERIN, restricts the release of measles virus from infected cells.Virus Res. 2019 Apr 2;263:145-150. doi: 10.1016/j.virusres.2019.01.014. Epub 2019 Jan 23.
• [6] Involvement of viperin in prevention of intrauterine transmission of hepatitis B virus.APMIS. 2017 Feb;125(2):170-175. doi: 10.1111/apm.12630. Epub 2016 Dec 12.
• [7] A naturally occurring antiviral ribonucleotide encoded by the human genome.Nature. 2018 Jun;558(7711):610-614. doi: 10.1038/s41586-018-0238-4. Epub 2018 Jun 20.
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• [9] Intrinsic expression of viperin regulates thermogenesis in adipose tissues.Proc Natl Acad Sci U S A. 2019 Aug 27;116(35):17419-17428. doi: 10.1073/pnas.1904480116. Epub 2019 Jul 24.
• [10] Cardioplegia prevents ischemia-induced transcriptional alterations of cytoprotective genes in rat hearts: a DNA microarray study.J Thorac Cardiovasc Surg. 2005 Oct;130(4):1151. doi: 10.1016/j.jtcvs.2005.06.027.
• [11] Progressive glomerular and tubular damage in sickle cell trait and sickle cell anemia mouse models.Transl Res. 2018 Jul;197:1-11. doi: 10.1016/j.trsl.2018.01.007. Epub 2018 Feb 2.
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• [13] A Viperin Mutant Bearing the K358R Substitution Lost its Anti-ZIKA Virus Activity.Int J Mol Sci. 2019 Mar 29;20(7):1574. doi: 10.3390/ijms20071574.
• [14] The interferon stimulated gene viperin, restricts Shigella. flexneri in vitro.Sci Rep. 2019 Oct 30;9(1):15598. doi: 10.1038/s41598-019-52130-8.
• [15] Reduced sputum expression of interferon-stimulated genes in severe COPD.Int J Chron Obstruct Pulmon Dis. 2016 Jun 30;11:1485-94. doi: 10.2147/COPD.S105948. eCollection 2016.
• [16] A genome-wide search for common SNP x SNP interactions on the risk of venous thrombosis.BMC Med Genet. 2013 Mar 20;14:36. doi: 10.1186/1471-2350-14-36.
• [17] Raised interferon-, type 3 interferon and interferon-stimulated genes - evidence of innate immune activation in neutrophilic asthma.Clin Exp Allergy. 2017 Mar;47(3):313-323. doi: 10.1111/cea.12809. Epub 2016 Oct 14.
• [18] RSAD2 and AIM2 Modulate Coxsackievirus A16 and Enterovirus A71 Replication in Neuronal Cells in Different Ways That May Be Associated with Their 5' Nontranslated Regions.J Virol. 2018 Feb 26;92(6):e01914-17. doi: 10.1128/JVI.01914-17. Print 2018 Mar 15.
• [19] Whole-exome sequencing uncovers oxidoreductases DHTKD1 and OGDHL as linkers between mitochondrial dysfunction and eosinophilic esophagitis.JCI Insight. 2018 Apr 19;3(8):e99922. doi: 10.1172/jci.insight.99922. eCollection 2018 Apr 19.
• [20] Weighted gene correlation network analysis identifies RSAD2, HERC5, and CCL8 as prognostic candidates for breast cancer.J Cell Physiol. 2020 Jan;235(1):394-407. doi: 10.1002/jcp.28980. Epub 2019 Jun 21.
• [21] 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.
• [22] Integrative "-Omics" analysis in primary human hepatocytes unravels persistent mechanisms of cyclosporine A-induced cholestasis. Chem Res Toxicol. 2016 Dec 19;29(12):2164-2174.
• [23] 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.
• [24] 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.
• [25] 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.
• [26] Persistent and non-persistent changes in gene expression result from long-term estrogen exposure of MCF-7 breast cancer cells. J Steroid Biochem Mol Biol. 2011 Feb;123(3-5):140-50.
• [27] Hypoxia-inducible factor-1 (HIF-1) pathway activation by quercetin in human lens epithelial cells. Exp Eye Res. 2009 Dec;89(6):995-1002. doi: 10.1016/j.exer.2009.08.011. Epub 2009 Sep 1.
• [28] 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.
• [29] Large-scale in silico and microarray-based identification of direct 1,25-dihydroxyvitamin D3 target genes. Mol Endocrinol. 2005 Nov;19(11):2685-95.
• [30] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [31] Transcriptional profiling of testosterone-regulated genes in the skeletal muscle of human immunodeficiency virus-infected men experiencing weight loss. J Clin Endocrinol Metab. 2007 Jul;92(7):2793-802. doi: 10.1210/jc.2006-2722. Epub 2007 Apr 17.
• [32] Exposure to Insecticides Modifies Gene Expression and DNA Methylation in Hematopoietic Tissues In Vitro. Int J Mol Sci. 2023 Mar 26;24(7):6259. doi: 10.3390/ijms24076259.
• [33] White-to-brown metabolic conversion of human adipocytes by JAK inhibition. Nat Cell Biol. 2015 Jan;17(1):57-67. doi: 10.1038/ncb3075. Epub 2014 Dec 8.
• [34] 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.
• [35] Resveratrol inhibits pancreatic cancer cell proliferation through transcriptional induction of macrophage inhibitory cytokine-1. J Surg Res. 2007 Apr;138(2):163-9. doi: 10.1016/j.jss.2006.05.037. Epub 2007 Jan 25.
• [36] Transcriptional signature of human macrophages exposed to the environmental contaminant benzo(a)pyrene. Toxicol Sci. 2010 Apr;114(2):247-59.
• [37] Regulation of chromatin assembly and cell transformation by formaldehyde exposure in human cells. Environ Health Perspect. 2017 Sep 21;125(9):097019.
• [38] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.