Details of Drug Off-Target (DOT)

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

• DOT Name: Negative elongation factor C/D (NELFCD)
• Synonyms: NELF-C/D; TH1-like protein
• Gene Name: NELFCD
• Related Disease:
  Visceral leishmaniasis
  Coeliac disease
  Colorectal carcinoma
  Helminth infection
  Hypersensitivity pneumonitis
  Lung neoplasm
  Lyme disease
  Neoplasm
  Pneumonia
  Pneumonitis
  Primary biliary cholangitis
  Pyoderma gangrenosum
  Sweetener
  Thrombocytopenia 1
  Wiskott-Aldrich syndrome
  Rheumatoid arthritis
  Type-1 diabetes
• UniProt ID: NELFD_HUMAN
• PDB ID: 5L3X; 6GML; 7PKS; 7YCX
• Pfam ID: PF04858
• Sequence:
  MAGAVPGAIMDEDYYGSAAEWGDEADGGQQEDDSGEGEDDAEVQQECLHKFSTRDYIMEP
  SIFNTLKRYFQAGGSPENVIQLLSENYTAVAQTVNLLAEWLIQTGVEPVQVQETVENHLK
  SLLIKHFDPRKADSIFTEEGETPAWLEQMIAHTTWRDLFYKLAEAHPDCLMLNFTVKLIS
  DAGYQGEITSVSTACQQLEVFSRVLRTSLATILDGGEENLEKNLPEFAKMVCHGEHTYLF
  AQAMMSVLAQEEQGGSAVRRIAQEVQRFAQEKGHDASQITLALGTAASYPRACQALGAML
  SKGALNPADITVLFKMFTSMDPPPVELIRVPAFLDLFMQSLFKPGARINQDHKHKYIHIL
  AYAASVVETWKKNKRVSINKDELKSTSKAVETVHNLCCNENKGASELVAELSTLYQCIRF
  PVVAMGVLKWVDWTVSEPRYFQLQTDHTPVHLALLDEISTCHQLLHPQVLQLLVKLFETE
  HSQLDVMEQLELKKTLLDRMVHLLSRGYVLPVVSYIRKCLEKLDTDISLIRYFVTEVLDV
  IAPPYTSDFVQLFLPILENDSIAGTIKTEGEHDPVTEFIAHCKSNFIMVN
• Function: Essential component of the NELF complex, a complex that negatively regulates the elongation of transcription by RNA polymerase II. The NELF complex, which acts via an association with the DSIF complex and causes transcriptional pausing, is counteracted by the P-TEFb kinase complex ; (Microbial infection) The NELF complex is involved in HIV-1 latency possibly involving recruitment of PCF11 to paused RNA polymerase II.
• Tissue Specificity: Widely expressed. Expressed in heart, brain, lung, placenta, liver, skeletal and cardiac muscle, adrenal, thyroid, kidney and pancreas.
• KEGG Pathway: Viral life cycle - HIV-1 (hsa03250)
• Reactome Pathway:
  Formation of the Early Elongation Complex (R-HSA-113418)
  Formation of HIV elongation complex in the absence of HIV Tat (R-HSA-167152)
  Formation of the HIV-1 Early Elongation Complex (R-HSA-167158)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Abortive elongation of HIV-1 transcript in the absence of Tat (R-HSA-167242)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  HIV elongation arrest and recovery (R-HSA-167287)
  Pausing and recovery of HIV elongation (R-HSA-167290)
  RNA Polymerase II Pre-transcription Events (R-HSA-674695)
  TP53 Regulates Transcription of DNA Repair Genes (R-HSA-6796648)
  RNA Polymerase II Transcription Elongation (R-HSA-75955)
  Formation of RNA Pol II elongation complex (R-HSA-112382)

Molecular Interaction Atlas (MIA) of This DOT

17 Disease(s) Related to This DOT

Disease Name	Disease ID	Evidence Level	Mode of Inheritance	REF
Visceral leishmaniasis	DISTKEYK	Definitive	Biomarker	[1]
Coeliac disease	DISIY60C	Strong	Altered Expression	[2]
Colorectal carcinoma	DIS5PYL0	Strong	Altered Expression	[3]
Helminth infection	DIS7CGKY	Strong	Altered Expression	[4]
Hypersensitivity pneumonitis	DIS5IW5K	Strong	Altered Expression	[5]
Lung neoplasm	DISVARNB	Strong	Altered Expression	[6]
Lyme disease	DISO70G5	Strong	Biomarker	[7]
Neoplasm	DISZKGEW	Strong	Altered Expression	[3]
Pneumonia	DIS8EF3M	Strong	Altered Expression	[5]
Pneumonitis	DIS88E0K	Strong	Altered Expression	[5]
Primary biliary cholangitis	DIS43E0O	Strong	Genetic Variation	[8]
Pyoderma gangrenosum	DIS8QVTT	Strong	Altered Expression	[9]
Sweetener	DISDGALM	Strong	Altered Expression	[9]
Thrombocytopenia 1	DISTC3AW	Strong	Genetic Variation	[10]
Wiskott-Aldrich syndrome	DISATMDB	Strong	Genetic Variation	[10]
Rheumatoid arthritis	DISTSB4J	Limited	Biomarker	[11]
Type-1 diabetes	DIS7HLUB	Limited	Biomarker	[12]

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

Drug Name	Drug ID	Highest Status	Interaction	REF
Valproate	DMCFE9I	Approved	Valproate decreases the expression of Negative elongation factor C/D (NELFCD).	[13]
Acetaminophen	DMUIE76	Approved	Acetaminophen decreases the expression of Negative elongation factor C/D (NELFCD).	[14]
Ivermectin	DMDBX5F	Approved	Ivermectin decreases the expression of Negative elongation factor C/D (NELFCD).	[15]
Carbamazepine	DMZOLBI	Approved	Carbamazepine affects the expression of Negative elongation factor C/D (NELFCD).	[16]
PMID28460551-Compound-2	DM4DOUB	Patented	PMID28460551-Compound-2 decreases the expression of Negative elongation factor C/D (NELFCD).	[17]

References

• [1] HIF-1 hampers dendritic cell function and Th1 generation during chronic visceral leishmaniasis.Sci Rep. 2018 Feb 22;8(1):3500. doi: 10.1038/s41598-018-21891-z.
• [2] The effect of gluten-free diet on Th1-Th2-Th3-associated intestinal immune responses in celiac disease.Scand J Gastroenterol. 2011 May;46(5):538-49. doi: 10.3109/00365521.2011.551888. Epub 2011 Feb 3.
• [3] Overexpression of NELFCD promotes colorectal cancer cells proliferation, migration, and invasion.Onco Targets Ther. 2018 Dec 5;11:8741-8750. doi: 10.2147/OTT.S186266. eCollection 2018.
• [4] Differential changes in expression of intestinal antimicrobial peptide genes during Ascaris lumbricoides infection in Zambian adults do not respond to helminth eradication.J Infect Dis. 2011 May 15;203(10):1464-73. doi: 10.1093/infdis/jir035. Epub 2011 Feb 28.
• [5] Interleukin-17A and Neutrophils in a Murine Model of Bird-Related Hypersensitivity Pneumonitis.PLoS One. 2015 Sep 14;10(9):e0137978. doi: 10.1371/journal.pone.0137978. eCollection 2015.
• [6] FAM13A is associated with non-small cell lung cancer (NSCLC) progression and controls tumor cell proliferation and survival.Oncoimmunology. 2016 Dec 14;6(1):e1256526. doi: 10.1080/2162402X.2016.1256526. eCollection 2017.
• [7] Decreased up-regulation of the interleukin-12Rbeta2-chain and interferon-gamma secretion and increased number of forkhead box P3-expressing cells in patients with a history of chronic Lyme borreliosis compared with asymptomatic Borrelia-exposed individuals.Clin Exp Immunol. 2007 Jan;147(1):18-27. doi: 10.1111/j.1365-2249.2006.03245.x.
• [8] Increased expression and altered localization of cathepsin Z are associated with progression to jaundice stage in primary biliary cholangitis.Sci Rep. 2018 Aug 7;8(1):11808. doi: 10.1038/s41598-018-30146-w.
• [9] T helper type 1-related molecules as well as interleukin-15 are hyperexpressed in the skin lesions of patients with pyoderma gangrenosum.Clin Exp Immunol. 2017 Sep;189(3):383-391. doi: 10.1111/cei.12989. Epub 2017 Jun 23.
• [10] Disruption of hSWI/SNF complexes in T cells by WAS mutations distinguishes X-linked thrombocytopenia from Wiskott-Aldrich syndrome.Blood. 2014 Nov 27;124(23):3409-19. doi: 10.1182/blood-2014-07-587642. Epub 2014 Sep 24.
• [11] Role of IL-17 in the Th1 systemic defects in rheumatoid arthritis through selective IL-12Rbeta2 inhibition.Ann Rheum Dis. 2010 Aug;69(8):1562-7. doi: 10.1136/ard.2009.111757. Epub 2010 Jun 11.
• [12] Expression levels of CXC chemokine receptors 3 are associated with clinical phenotype of type 1 diabetes.Ann N Y Acad Sci. 2006 Oct;1079:186-9. doi: 10.1196/annals.1375.029.
• [13] The neuroprotective action of the mood stabilizing drugs lithium chloride and sodium valproate is mediated through the up-regulation of the homeodomain protein Six1. Toxicol Appl Pharmacol. 2009 Feb 15;235(1):124-34.
• [14] Multiple microRNAs function as self-protective modules in acetaminophen-induced hepatotoxicity in humans. Arch Toxicol. 2018 Feb;92(2):845-858.
• [15] 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.
• [16] Gene Expression Regulation and Pathway Analysis After Valproic Acid and Carbamazepine Exposure in a Human Embryonic Stem Cell-Based Neurodevelopmental Toxicity Assay. Toxicol Sci. 2015 Aug;146(2):311-20. doi: 10.1093/toxsci/kfv094. Epub 2015 May 15.
• [17] 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.