Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTFIIC43)

• DOT Name: Antiviral innate immune response receptor RIG-I (RIGI)
• Synonyms: ATP-dependent RNA helicase DDX58; EC 3.6.4.13; DEAD box protein 58; RIG-I-like receptor 1; RLR-1; RNA sensor RIG-I; Retinoic acid-inducible gene 1 protein; RIG-1; Retinoic acid-inducible gene I protein; RIG-I
• Gene Name: RIGI
• Related Disease:
  Singleton-Merten syndrome 2
  Singleton-Merten dysplasia
  Singleton-Merten syndrome 1
• UniProt ID: RIGI_HUMAN
• PDB ID: 2LWD ; 2LWE ; 2QFB ; 2QFD ; 2RMJ ; 2YKG ; 3LRN ; 3LRR ; 3NCU ; 3OG8 ; 3ZD6 ; 3ZD7 ; 4AY2 ; 4BPB ; 4NQK ; 4ON9 ; 4P4H ; 5E3H ; 5F98 ; 5F9F ; 5F9H ; 6GPG ; 6KYV ; 7BAH ; 7BAI ; 7JL1 ; 7JL3 ; 7MK1 ; 7TNX ; 7TNY ; 7TNZ ; 7TO0 ; 7TO1 ; 7TO2 ; 8DVR ; 8DVS ; 8DVU ; 8G7T ; 8G7U ; 8G7V
• EC Number: 3.6.4.13
• Pfam ID: PF16739 ; PF00270 ; PF00271 ; PF18119 ; PF11648
• Sequence:
  MTTEQRRSLQAFQDYIRKTLDPTYILSYMAPWFREEEVQYIQAEKNNKGPMEAATLFLKF
  LLELQEEGWFRGFLDALDHAGYSGLYEAIESWDFKKIEKLEEYRLLLKRLQPEFKTRIIP
  TDIISDLSECLINQECEEILQICSTKGMMAGAEKLVECLLRSDKENWPKTLKLALEKERN
  KFSELWIVEKGIKDVETEDLEDKMETSDIQIFYQEDPECQNLSENSCPPSEVSDTNLYSP
  FKPRNYQLELALPAMKGKNTIICAPTGCGKTFVSLLICEHHLKKFPQGQKGKVVFFANQI
  PVYEQQKSVFSKYFERHGYRVTGISGATAENVPVEQIVENNDIIILTPQILVNNLKKGTI
  PSLSIFTLMIFDECHNTSKQHPYNMIMFNYLDQKLGGSSGPLPQVIGLTASVGVGDAKNT
  DEALDYICKLCASLDASVIATVKHNLEELEQVVYKPQKFFRKVESRISDKFKYIIAQLMR
  DTESLAKRICKDLENLSQIQNREFGTQKYEQWIVTVQKACMVFQMPDKDEESRICKALFL
  YTSHLRKYNDALIISEHARMKDALDYLKDFFSNVRAAGFDEIEQDLTQRFEEKLQELESV
  SRDPSNENPKLEDLCFILQEEYHLNPETITILFVKTRALVDALKNWIEGNPKLSFLKPGI
  LTGRGKTNQNTGMTLPAQKCILDAFKASGDHNILIATSVADEGIDIAQCNLVILYEYVGN
  VIKMIQTRGRGRARGSKCFLLTSNAGVIEKEQINMYKEKMMNDSILRLQTWDEAVFREKI
  LHIQTHEKFIRDSQEKPKPVPDKENKKLLCRKCKALACYTADVRVIEECHYTVLGDAFKE
  CFVSRPHPKPKQFSSFEKRAKIFCARQNCSHDWGIHVKYKTFEIPVIKIESFVVEDIATG
  VQTLYSKWKDFHFEKIPFDPAEMSK
• Function: Innate immune receptor that senses cytoplasmic viral nucleic acids and activates a downstream signaling cascade leading to the production of type I interferons and pro-inflammatory cytokines. Forms a ribonucleoprotein complex with viral RNAs on which it homooligomerizes to form filaments. The homooligomerization allows the recruitment of RNF135 an E3 ubiquitin-protein ligase that activates and amplifies the RIG-I-mediated antiviral signaling in an RNA length-dependent manner through ubiquitination-dependent and -independent mechanisms. Upon activation, associates with mitochondria antiviral signaling protein (MAVS/IPS1) that activates the IKK-related kinases TBK1 and IKBKE which in turn phosphorylate the interferon regulatory factors IRF3 and IRF7, activating transcription of antiviral immunological genes including the IFN-alpha and IFN-beta interferons. Ligands include 5'-triphosphorylated ssRNAs and dsRNAs but also short dsRNAs (<1 kb in length). In addition to the 5'-triphosphate moiety, blunt-end base pairing at the 5'-end of the RNA is very essential. Overhangs at the non-triphosphorylated end of the dsRNA RNA have no major impact on its activity. A 3'overhang at the 5'triphosphate end decreases and any 5'overhang at the 5' triphosphate end abolishes its activity. Detects both positive and negative strand RNA viruses including members of the families Paramyxoviridae: Human respiratory syncytial virus and measles virus (MeV), Rhabdoviridae: vesicular stomatitis virus (VSV), Orthomyxoviridae: influenza A and B virus, Flaviviridae: Japanese encephalitis virus (JEV), hepatitis C virus (HCV), dengue virus (DENV) and west Nile virus (WNV). It also detects rotaviruses and reoviruses. Detects and binds to SARS-CoV-2 RNAs which is inhibited by m6A RNA modifications (Ref.69). Also involved in antiviral signaling in response to viruses containing a dsDNA genome such as Epstein-Barr virus (EBV). Detects dsRNA produced from non-self dsDNA by RNA polymerase III, such as Epstein-Barr virus-encoded RNAs (EBERs). May play important roles in granulocyte production and differentiation, bacterial phagocytosis and in the regulation of cell migration.
• Tissue Specificity: Present in vascular smooth cells (at protein level).
• KEGG Pathway:
  NF-kappa B sig.ling pathway (hsa04064)
  RIG-I-like receptor sig.ling pathway (hsa04622)
  Cytosolic D.-sensing pathway (hsa04623)
  Hepatitis C (hsa05160)
  Hepatitis B (hsa05161)
  Measles (hsa05162)
  Influenza A (hsa05164)
  Herpes simplex virus 1 infection (hsa05168)
  Epstein-Barr virus infection (hsa05169)
  Coro.virus disease - COVID-19 (hsa05171)
• Reactome Pathway:
  DDX58/IFIH1-mediated induction of interferon-alpha/beta (R-HSA-168928)
  Ub-specific processing proteases (R-HSA-5689880)
  Ovarian tumor domain proteases (R-HSA-5689896)
  OAS antiviral response (R-HSA-8983711)
  TRAF3-dependent IRF activation pathway (R-HSA-918233)
  TRAF6 mediated IRF7 activation (R-HSA-933541)
  TRAF6 mediated NF-kB activation (R-HSA-933542)
  NF-kB activation through FADD/RIP-1 pathway mediated by caspase-8 and -10 (R-HSA-933543)
  Negative regulators of DDX58/IFIH1 signaling (R-HSA-936440)
  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

3 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Singleton-Merten syndrome 2	DISBYX0D	Strong	Autosomal dominant	[1]
Singleton-Merten dysplasia	DISYNAVB	Supportive	Autosomal dominant	[1]
Singleton-Merten syndrome 1	DISXY2LC	Limited	Autosomal dominant	[1]

1 Drug(s) Affected the Post-Translational Modifications of This DOT

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the methylation of Antiviral innate immune response receptor RIG-I (RIGI).	[2]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Ciclosporin	DMAZJFX	Approved	Ciclosporin increases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[6]
Cupric Sulfate	DMP0NFQ	Approved	Cupric Sulfate increases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[7]
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[8]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[9]
Quercetin	DM3NC4M	Approved	Quercetin decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[10]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[11]
Methotrexate	DM2TEOL	Approved	Methotrexate decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[12]
Azathioprine	DMMZSXQ	Approved	Azathioprine decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[12]
Diclofenac	DMPIHLS	Approved	Diclofenac decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[12]
Piroxicam	DMTK234	Approved	Piroxicam decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[12]
Prednisolone	DMQ8FR2	Approved	Prednisolone decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[12]
Methylprednisolone	DM4BDON	Approved	Methylprednisolone decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[12]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[13]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 increases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[14]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A decreases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[16]
Sulforaphane	DMQY3L0	Investigative	Sulforaphane increases the expression of Antiviral innate immune response receptor RIG-I (RIGI).	[17]

References

• [1] Mutations in DDX58, which encodes RIG-I, cause atypical Singleton-Merten syndrome. Am J Hum Genet. 2015 Feb 5;96(2):266-74. doi: 10.1016/j.ajhg.2014.11.019. Epub 2015 Jan 22.
• [2] 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.
• [3] Cyclosporine A--induced oxidative stress in human renal mesangial cells: a role for ERK 1/2 MAPK signaling. Toxicol Sci. 2012 Mar;126(1):101-13.
• [4] Benzodithiophenes potentiate differentiation of acute promyelocytic leukemia cells by lowering the threshold for ligand-mediated corepressor/coactivator exchange with retinoic acid receptor alpha and enhancing changes in all-trans-retinoic acid-regulated gene expression. Cancer Res. 2005 Sep 1;65(17):7856-65. doi: 10.1158/0008-5472.CAN-05-1056.
• [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] Physiological and toxicological transcriptome changes in HepG2 cells exposed to copper. Physiol Genomics. 2009 Aug 7;38(3):386-401.
• [8] 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.
• [9] 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.
• [10] 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.
• [11] 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.
• [12] Antirheumatic drug response signatures in human chondrocytes: potential molecular targets to stimulate cartilage regeneration. Arthritis Res Ther. 2009;11(1):R15.
• [13] Genome-wide transcriptional and functional analysis of human T lymphocytes treated with benzo[alpha]pyrene. Int J Mol Sci. 2018 Nov 17;19(11).
• [14] 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.
• [15] Environmental pollutant induced cellular injury is reflected in exosomes from placental explants. Placenta. 2020 Jan 1;89:42-49. doi: 10.1016/j.placenta.2019.10.008. Epub 2019 Oct 17.
• [16] 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.
• [17] Transcriptome and DNA methylation changes modulated by sulforaphane induce cell cycle arrest, apoptosis, DNA damage, and suppression of proliferation in human liver cancer cells. Food Chem Toxicol. 2020 Feb;136:111047. doi: 10.1016/j.fct.2019.111047. Epub 2019 Dec 12.