Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT19BYB1)

• DOT Name: ATP-dependent RNA helicase DHX58 (DHX58)
• Synonyms: EC 3.6.4.13; ATP-dependent helicase LGP2; Protein D11Lgp2 homolog; RIG-I-like receptor 3; RLR-3; RIG-I-like receptor LGP2; RLR
• Gene Name: DHX58
• Related Disease:
  Advanced cancer
  Colorectal carcinoma
  Hepatitis
  Hepatitis A virus infection
  Influenza
  Multiple sclerosis
  Neoplasm
  Neuroblastoma
  Coronary heart disease
  Pancreatic ductal carcinoma
  Picornaviridae infectious disease
  Autoimmune disease
  Encephalitis
  Hepatitis C virus infection
• UniProt ID: DHX58_HUMAN
• PDB ID: 2RQA; 2W4R; 3EQT
• EC Number: 3.6.4.13
• Pfam ID: PF00271 ; PF04851 ; PF18119 ; PF11648
• Sequence:
  MELRSYQWEVIMPALEGKNIIIWLPTGAGKTRAAAYVAKRHLETVDGAKVVVLVNRVHLV
  TQHGEEFRRMLDGRWTVTTLSGDMGPRAGFGHLARCHDLLICTAELLQMALTSPEEEEHV
  ELTVFSLIVVDECHHTHKDTVYNVIMSQYLELKLQRAQPLPQVLGLTASPGTGGASKLDG
  AINHVLQLCANLDTWCIMSPQNCCPQLQEHSQQPCKQYNLCHRRSQDPFGDLLKKLMDQI
  HDHLEMPELSRKFGTQMYEQQVVKLSEAAALAGLQEQRVYALHLRRYNDALLIHDTVRAV
  DALAALQDFYHREHVTKTQILCAERRLLALFDDRKNELAHLATHGPENPKLEMLEKILQR
  QFSSSNSPRGIIFTRTRQSAHSLLLWLQQQQGLQTVDIRAQLLIGAGNSSQSTHMTQRDQ
  QEVIQKFQDGTLNLLVATSVAEEGLDIPHCNVVVRYGLLTNEISMVQARGRARADQSVYA
  FVATEGSRELKRELINEALETLMEQAVAAVQKMDQAEYQAKIRDLQQAALTKRAAQAAQR
  ENQRQQFPVEHVQLLCINCMVAVGHGSDLRKVEGTHHVNVNPNFSNYYNVSRDPVVINKV
  FKDWKPGGVISCRNCGEVWGLQMIYKSVKLPVLKVRSMLLETPQGRIQAKKWSRVPFSVP
  DFDFLQHCAENLSDLSLD
• Function: Acts as a regulator of RIGI and IFIH1/MDA5 mediated antiviral signaling. Cannot initiate antiviral signaling as it lacks the CARD domain required for activating MAVS/IPS1-dependent signaling events. Can have both negative and positive regulatory functions related to RIGI and IFIH1/MDA5 signaling and this role in regulating signaling may be complex and could probably depend on characteristics of the infecting virus or target cells, or both. Its inhibitory action on RIG-I signaling may involve the following mechanisms: competition with RIGI for binding to the viral RNA, binding to RIGI and inhibiting its dimerization and interaction with MAVS/IPS1, competing with IKBKE in its binding to MAVS/IPS1 thereby inhibiting activation of interferon regulatory factor 3 (IRF3). Its positive regulatory role may involve unwinding or stripping nucleoproteins of viral RNA thereby facilitating their recognition by RIGI and IFIH1/MDA5. Involved in the innate immune response to various RNA viruses and some DNA viruses such as poxviruses and coronavirus SARS-CoV-2, and also to the bacterial pathogen Listeria monocytogenes. Can bind both ssRNA and dsRNA, with a higher affinity for dsRNA. Shows a preference to 5'-triphosphorylated RNA, although it can recognize RNA lacking a 5'-triphosphate.
• Tissue Specificity: Expressed in testis, nerve and spleen. Also expressed in the brain.
• KEGG Pathway: RIG-I-like receptor sig.ling pathway (hsa04622)
• Reactome Pathway: DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)

Molecular Interaction Atlas (MIA) of This DOT

14 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Advanced cancer	DISAT1Z9	Strong	Biomarker	[1]
Colorectal carcinoma	DIS5PYL0	Strong	Biomarker	[2]
Hepatitis	DISXXX35	Strong	Biomarker	[3]
Hepatitis A virus infection	DISUMFQV	Strong	Biomarker	[3]
Influenza	DIS3PNU3	Strong	Biomarker	[4]
Multiple sclerosis	DISB2WZI	Strong	Genetic Variation	[5]
Neoplasm	DISZKGEW	Strong	Altered Expression	[1]
Neuroblastoma	DISVZBI4	Strong	Biomarker	[1]
Coronary heart disease	DIS5OIP1	moderate	Genetic Variation	[6]
Pancreatic ductal carcinoma	DIS26F9Q	moderate	Biomarker	[7]
Picornaviridae infectious disease	DISC80MD	moderate	Biomarker	[8]
Autoimmune disease	DISORMTM	Disputed	Biomarker	[9]
Encephalitis	DISLD1RL	Disputed	Biomarker	[9]
Hepatitis C virus infection	DISQ0M8R	Limited	Biomarker	[10]

3 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 ATP-dependent RNA helicase DHX58 (DHX58).	[11]
Arsenic	DMTL2Y1	Approved	Arsenic affects the methylation of ATP-dependent RNA helicase DHX58 (DHX58).	[17]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of ATP-dependent RNA helicase DHX58 (DHX58).	[21]

9 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 ATP-dependent RNA helicase DHX58 (DHX58).	[12]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of ATP-dependent RNA helicase DHX58 (DHX58).	[13]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of ATP-dependent RNA helicase DHX58 (DHX58).	[14]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of ATP-dependent RNA helicase DHX58 (DHX58).	[15]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of ATP-dependent RNA helicase DHX58 (DHX58).	[16]
Triclosan	DMZUR4N	Approved	Triclosan increases the expression of ATP-dependent RNA helicase DHX58 (DHX58).	[18]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of ATP-dependent RNA helicase DHX58 (DHX58).	[19]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of ATP-dependent RNA helicase DHX58 (DHX58).	[20]
Acetaldehyde	DMJFKG4	Investigative	Acetaldehyde increases the expression of ATP-dependent RNA helicase DHX58 (DHX58).	[22]

References

• [1] Innate immune sensor laboratory of genetics and physiology 2 suppresses tumor cell growth and functions as a prognostic marker in neuroblastoma.Cancer Sci. 2018 Nov;109(11):3494-3502. doi: 10.1111/cas.13790. Epub 2018 Oct 4.
• [2] The epigenetic modifier PBRM1 restricts the basal activity of the innate immune system by repressing retinoic acid-inducible gene-I-like receptor signalling and is a potential prognostic biomarker for colon cancer.J Pathol. 2018 Jan;244(1):36-48. doi: 10.1002/path.4986. Epub 2017 Nov 27.
• [3] New Techniques to Study Intracellular Receptors in Living Cells: Insights Into RIG-I-Like Receptor Signaling.Adv Exp Med Biol. 2019;1111:219-240. doi: 10.1007/5584_2018_297.
• [4] LGP2 downregulates interferon production during infection with seasonal human influenza A viruses that activate interferon regulatory factor 3.J Virol. 2012 Oct;86(19):10733-8. doi: 10.1128/JVI.00510-12. Epub 2012 Jul 25.
• [5] Analysis of polymorphisms in RIG-I-like receptor genes in German multiple sclerosis patients.J Neuroimmunol. 2014 Dec 15;277(1-2):140-4. doi: 10.1016/j.jneuroim.2014.09.015. Epub 2014 Sep 28.
• [6] Identification of 64 Novel Genetic Loci Provides an Expanded View on the Genetic Architecture of Coronary Artery Disease.Circ Res. 2018 Feb 2;122(3):433-443. doi: 10.1161/CIRCRESAHA.117.312086. Epub 2017 Dec 6.
• [7] Pancreatic cancer-specific cell death induced in vivo by cytoplasmic-delivered polyinosine-polycytidylic acid.Cancer Res. 2014 Nov 1;74(21):6224-35. doi: 10.1158/0008-5472.CAN-14-0819. Epub 2014 Sep 9.
• [8] Innate immune sensor LGP2 is cleaved by the Leader protease of foot-and-mouth disease virus.PLoS Pathog. 2018 Jun 29;14(6):e1007135. doi: 10.1371/journal.ppat.1007135. eCollection 2018 Jun.
• [9] PACT is required for MDA5-mediated immunoresponses triggered by Cardiovirus infection via interaction with LGP2.Biochem Biophys Res Commun. 2017 Dec 9;494(1-2):227-233. doi: 10.1016/j.bbrc.2017.10.048. Epub 2017 Oct 12.
• [10] Laboratory of genetics and physiology 2 (LGP2) plays an essential role in hepatitis C virus infection-induced interferon responses.Hepatology. 2017 May;65(5):1478-1491. doi: 10.1002/hep.29050. Epub 2017 Mar 30.
• [11] 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.
• [12] Retinoic acid receptor alpha amplifications and retinoic acid sensitivity in breast cancers. Clin Breast Cancer. 2013 Oct;13(5):401-8.
• [13] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [14] 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.
• [15] Low doses of cisplatin induce gene alterations, cell cycle arrest, and apoptosis in human promyelocytic leukemia cells. Biomark Insights. 2016 Aug 24;11:113-21.
• [16] 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.
• [17] Prenatal arsenic exposure and the epigenome: identifying sites of 5-methylcytosine alterations that predict functional changes in gene expression in newborn cord blood and subsequent birth outcomes. Toxicol Sci. 2015 Jan;143(1):97-106. doi: 10.1093/toxsci/kfu210. Epub 2014 Oct 10.
• [18] Transcriptome and DNA methylome dynamics during triclosan-induced cardiomyocyte differentiation toxicity. Stem Cells Int. 2018 Oct 29;2018:8608327.
• [19] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [20] A transcriptome-based classifier to identify developmental toxicants by stem cell testing: design, validation and optimization for histone deacetylase inhibitors. Arch Toxicol. 2015 Sep;89(9):1599-618.
• [21] Air pollution and DNA methylation alterations in lung cancer: A systematic and comparative study. Oncotarget. 2017 Jan 3;8(1):1369-1391. doi: 10.18632/oncotarget.13622.
• [22] Transcriptome profile analysis of saturated aliphatic aldehydes reveals carbon number-specific molecules involved in pulmonary toxicity. Chem Res Toxicol. 2014 Aug 18;27(8):1362-70.