Details of Drug Off-Target (DOT)

General Information of Drug Off-Target (DOT) (ID: OTZ4771K)

• DOT Name: Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL)
• Synonyms: SFL; SHFL; Interferon-regulated antiviral protein; IRAV; Repressor of yield of DENV protein; RyDEN
• Gene Name: SHFL
• Related Disease: Kaposi sarcoma
• UniProt ID: SHFL_HUMAN
• Pfam ID: PF15135
• Sequence:
  MSQEGVELEKSVRRLREKFHGKVSSKKAGALMRKFGSDHTGVGRSIVYGVKQKDGQELSN
  DLDAQDPPEDMKQDRDIQAVATSLLPLTEANLRMFQRAQDDLIPAVDRQFACSSCDHVWW
  RRVPQRKEVSRCRKCRKRYEPVPADKMWGLAEFHCPKCRHNFRGWAQMGSPSPCYGCGFP
  VYPTRILPPRWDRDPDRRSTHTHSCSAADCYNRREPHVPGTSCAHPKSRKQNHLPKVLHP
  SNPHISSGSTVATCLSQGGLLEDLDNLILEDLKEEEEEEEEVEDEEGGPRE
• Function: Inhibits programmed -1 ribosomal frameshifting (-1PRF) of a variety of mRNAs from viruses, such as HIV1, and cellular genes, such as PEG10. Interacts with the -1PRF signal of target mRNA and translating ribosomes and causes premature translation termination at the frameshifting site. Regulates HIV1 GAG-POL expression by inhibiting -1PRF. Exhibits antiviral activity against dengue virus (DENV) and can inhibit the replication of all DENV serotypes. May block the protein translation of DENV RNA via its association with cellular mRNA-binding proteins and viral RNA. Interrupts also Zika virus replication by promoting viral NS3 degradation via a lysosome-dependent pathway. Can also limit the replication of hepatitis C virus (HCV) by restricting formation of viral replication organelle, West Nile virus (WNV), Chikungunya virus (CHIKV), herpes simplex virus type 1 (HHV-1), herpes virus type 8 (HHV-8) and human adenovirus. Binds nucleic acids with a higher affinity for ssRNA and ssDNA than for dsDNA ; Isoform 4 does not inhibit programmed ribosomal frameshifting (-1PRF). Does not bind to ribosomes.

Molecular Interaction Atlas (MIA) of This DOT

1 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Kaposi sarcoma	DISC1H1Z	Definitive	Biomarker	[1]

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 Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[2]
Ciclosporin	DMAZJFX	Approved	Ciclosporin decreases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[3]
Tretinoin	DM49DUI	Approved	Tretinoin increases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[4]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[5]
Doxorubicin	DMVP5YE	Approved	Doxorubicin decreases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[6]
Cisplatin	DMRHGI9	Approved	Cisplatin increases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[7]
Temozolomide	DMKECZD	Approved	Temozolomide increases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[9]
Decitabine	DMQL8XJ	Approved	Decitabine affects the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[10]
Niclosamide	DMJAGXQ	Approved	Niclosamide increases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[11]
Urethane	DM7NSI0	Phase 4	Urethane decreases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[12]
SNDX-275	DMH7W9X	Phase 3	SNDX-275 increases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[13]
(+)-JQ1	DM1CZSJ	Phase 1	(+)-JQ1 decreases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[15]
Trichostatin A	DM9C8NX	Investigative	Trichostatin A increases the expression of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[16]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Arsenic	DMTL2Y1	Approved	Arsenic decreases the methylation of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[8]
Benzo(a)pyrene	DMN7J43	Phase 1	Benzo(a)pyrene increases the methylation of Shiftless antiviral inhibitor of ribosomal frameshifting protein (SHFL).	[14]

References

• [1] C19ORF66 Broadly Escapes Virus-Induced Endonuclease Cleavage and Restricts Kaposi's Sarcoma-Associated Herpesvirus.J Virol. 2019 May 29;93(12):e00373-19. doi: 10.1128/JVI.00373-19. Print 2019 Jun 15.
• [2] Human embryonic stem cell-derived test systems for developmental neurotoxicity: a transcriptomics approach. Arch Toxicol. 2013 Jan;87(1):123-43.
• [3] Integrating multiple omics to unravel mechanisms of Cyclosporin A induced hepatotoxicity in vitro. Toxicol In Vitro. 2015 Apr;29(3):489-501.
• [4] 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.
• [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] Activation of AIFM2 enhances apoptosis of human lung cancer cells undergoing toxicological stress. Toxicol Lett. 2016 Sep 6;258:227-236.
• [8] Association of Arsenic Exposure with Whole Blood DNA Methylation: An Epigenome-Wide Study of Bangladeshi Adults. Environ Health Perspect. 2019 May;127(5):57011. doi: 10.1289/EHP3849. Epub 2019 May 28.
• [9] 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.
• [10] Acute hypersensitivity of pluripotent testicular cancer-derived embryonal carcinoma to low-dose 5-aza deoxycytidine is associated with global DNA Damage-associated p53 activation, anti-pluripotency and DNA demethylation. PLoS One. 2012;7(12):e53003. doi: 10.1371/journal.pone.0053003. Epub 2012 Dec 27.
• [11] Mitochondrial Uncoupling Induces Epigenome Remodeling and Promotes Differentiation in Neuroblastoma. Cancer Res. 2023 Jan 18;83(2):181-194. doi: 10.1158/0008-5472.CAN-22-1029.
• [12] Ethyl carbamate induces cell death through its effects on multiple metabolic pathways. Chem Biol Interact. 2017 Nov 1;277:21-32.
• [13] 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.
• [14] 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.
• [15] Bromodomain-containing protein 4 (BRD4) regulates RNA polymerase II serine 2 phosphorylation in human CD4+ T cells. J Biol Chem. 2012 Dec 14;287(51):43137-55.
• [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.