Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OT3064D7)

• DOT Name: Syncytin-2 (ERVFRD-1)
• Synonyms: Endogenous retrovirus group FRD member 1; Envelope polyprotein; HERV-FRD; HERV-FRD_6p24.1 provirus ancestral Env polyprotein
• Gene Name: ERVFRD-1
• Related Disease:
  B-cell neoplasm
  Ewing sarcoma
  Multiple sclerosis
  Fetal growth restriction
  Adult glioblastoma
  Glioblastoma multiforme
  Hypertension, pregnancy-induced
• UniProt ID: SYCY2_HUMAN
• PDB ID: 1Y4M; 6RX3; 7OIX
• Pfam ID: PF00429
• Sequence:
  MGLLLLVLILTPSLAAYRHPDFPLLEKAQQLLQSTGSPYSTNCWLCTSSSTETPGTAYPA
  SPREWTSIEAELHISYRWDPNLKGLMRPANSLLSTVKQDFPDIRQKPPIFGPIFTNINLM
  GIAPICVMAKRKNGTNVGTLPSTVCNVTFTVDSNQQTYQTYTHNQFRHQPRFPKPPNITF
  PQGTLLDKSSRFCQGRPSSCSTRNFWFRPADYNQCLQISNLSSTAEWVLLDQTRNSLFWE
  NKTKGANQSQTPCVQVLAGMTIATSYLGISAVSEFFGTSLTPLFHFHISTCLKTQGAFYI
  CGQSIHQCLPSNWTGTCTIGYVTPDIFIAPGNLSLPIPIYGNSPLPRVRRAIHFIPLLAG
  LGILAGTGTGIAGITKASLTYSQLSKEIANNIDTMAKALTTMQEQIDSLAAVVLQNRRGL
  DMLTAAQGGICLALDEKCCFWVNQSGKVQDNIRQLLNQASSLRERATQGWLNWEGTWKWF
  SWVLPLTGPLVSLLLLLLFGPCLLNLITQFVSSRLQAIKLQTNLSAGRHPRNIQESPF
• Function: This endogenous retroviral envelope protein has retained its original fusogenic properties and participates in trophoblast fusion and the formation of a syncytium during placenta morphogenesis. The interaction with MFSD2A is apparently important for this process ; Endogenous envelope proteins may have kept, lost or modified their original function during evolution but this one can still make pseudotypes with MLV, HIV-1 or SIV-1 virions and confer infectivity. Retroviral envelope proteins mediate receptor recognition and membrane fusion during early infection. The surface protein mediates receptor recognition, while the transmembrane protein anchors the envelope heterodimer to the viral membrane through one transmembrane domain. The other hydrophobic domain, called fusion peptide, mediates fusion of the viral membrane with the target cell membrane.
• Tissue Specificity: Expressed at higher level in placenta. Expressed at lower level in adrenal, bone marrow, brain, breast, colon, kidney, lung, ovary, peripheral blood lymphocytes, prostate, skin, spleen, testis, thymus, thyroid, trachea.

Molecular Interaction Atlas (MIA) of This DOT

7 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
B-cell neoplasm	DISVY326	Strong	Altered Expression	[1]
Ewing sarcoma	DISQYLV3	Strong	Biomarker	[2]
Multiple sclerosis	DISB2WZI	Strong	Biomarker	[2]
Fetal growth restriction	DIS5WEJ5	moderate	Altered Expression	[3]
Adult glioblastoma	DISVP4LU	Limited	Biomarker	[4]
Glioblastoma multiforme	DISK8246	Limited	Biomarker	[4]
Hypertension, pregnancy-induced	DISHNU25	Limited	Biomarker	[5]

This DOT Affected the Drug Response of 3 Drug(s)

Drug Name	Drug ID	Highest Status	Interaction	REF
Cisplatin	DMRHGI9	Approved	Syncytin-2 (ERVFRD-1) affects the response to substance of Cisplatin.	[12]
Etoposide	DMNH3PG	Approved	Syncytin-2 (ERVFRD-1) affects the response to substance of Etoposide.	[12]
Mitomycin	DMH0ZJE	Approved	Syncytin-2 (ERVFRD-1) affects the response to substance of Mitomycin.	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Estradiol	DMUNTE3	Approved	Estradiol increases the expression of Syncytin-2 (ERVFRD-1).	[6]
Marinol	DM70IK5	Approved	Marinol decreases the expression of Syncytin-2 (ERVFRD-1).	[7]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the expression of Syncytin-2 (ERVFRD-1).	[8]
Bisphenol A	DM2ZLD7	Investigative	Bisphenol A increases the expression of Syncytin-2 (ERVFRD-1).	[6]
Milchsaure	DM462BT	Investigative	Milchsaure increases the expression of Syncytin-2 (ERVFRD-1).	[9]
Forskolin	DM6ITNG	Investigative	Forskolin increases the expression of Syncytin-2 (ERVFRD-1).	[10]
Anandamide	DMCKH3P	Investigative	Anandamide decreases the expression of Syncytin-2 (ERVFRD-1).	[11]

References

• [1] Formyl peptide receptor-2 is decreased in foetal growth restriction and contributes to placental dysfunction.Mol Hum Reprod. 2018 Feb 1;24(2):94-109. doi: 10.1093/molehr/gax067.
• [2] Investigation of Endogenous Retrovirus Sequences in the Neighborhood of Genes Up-regulated in a Neuroblastoma Model after Treatment with Hypoxia-Mimetic Cobalt Chloride.Front Microbiol. 2018 Feb 21;9:287. doi: 10.3389/fmicb.2018.00287. eCollection 2018.
• [3] Impaired cell fusion and differentiation in placentae from patients with intrauterine growth restriction correlate with reduced levels of HERV envelope genes.J Mol Med (Berl). 2010 Nov;88(11):1143-56. doi: 10.1007/s00109-010-0656-8. Epub 2010 Jul 28.
• [4] Cytotoxic stress induces transfer of mitochondria-associated human endogenous retroviral RNA and proteins between cancer cells.Oncotarget. 2017 Oct 7;8(56):95945-95964. doi: 10.18632/oncotarget.21606. eCollection 2017 Nov 10.
• [5] Cellular localization of placenta-specific human endogenous retrovirus (HERV) transcripts and their possible implication in pregnancy-induced hypertension.Placenta. 2008 Mar;29(3):282-9. doi: 10.1016/j.placenta.2007.11.009. Epub 2007 Dec 26.
• [6] Effects of Bisphenol A on endogenous retroviral envelopes expression and trophoblast fusion in BeWo cells. Reprod Toxicol. 2019 Oct;89:35-44. doi: 10.1016/j.reprotox.2019.07.001. Epub 2019 Jul 3.
• [7] The psychoactive compound of Cannabis sativa, (9)-tetrahydrocannabinol (THC) inhibits the human trophoblast cell turnover. Toxicology. 2015 Aug 6;334:94-103. doi: 10.1016/j.tox.2015.06.005. Epub 2015 Jun 9.
• [8] Differentiation of human placental BeWo cells by the environmental contaminant benzo(a)pyrene. Chem Biol Interact. 2014 Mar 5;210:1-11.
• [9] Transcriptional profiling of lactic acid treated reconstructed human epidermis reveals pathways underlying stinging and itch. Toxicol In Vitro. 2019 Jun;57:164-173.
• [10] Effects of selective serotonin-reuptake inhibitors (SSRIs) on human villous trophoblasts syncytialization. Toxicol Appl Pharmacol. 2018 Jun 15;349:8-20. doi: 10.1016/j.taap.2018.04.018. Epub 2018 Apr 19.
• [11] Anandamide down-regulates placental transporter expression through CB2 receptor-mediated inhibition of cAMP synthesis. Pharmacol Res. 2019 Mar;141:331-342. doi: 10.1016/j.phrs.2019.01.002. Epub 2019 Jan 2.
• [12] Gene expression profiling of 30 cancer cell lines predicts resistance towards 11 anticancer drugs at clinically achieved concentrations. Int J Cancer. 2006 Apr 1;118(7):1699-712. doi: 10.1002/ijc.21570.