Details of the Drug Therapeutic Target (DTT)

General Information of Drug Therapeutic Target (DTT) (ID: TTT3ZC9)

• DTT Name: Human immunodeficiency virus Tat protein (HIV tat)
• Synonyms: Transactivating regulatory protein; TAT protein
• Gene Name: HIV tat
• DTT Type: Successful target; [1]
• BioChemical Class: Lentiviruses Tat family
• UniProt ID: TAT_HV1H2
• TTD ID: T93783
• Sequence:
  MEPVDPRLEPWKHPGSQPKTACTNCYCKKCCFHCQVCFITKALGISYGRKKRRQRRRAHQ
  NSQTHQASLSKQPTSQPRGDPTGPKE
• Function: Extracellular circulating Tat can be endocytosed by surrounding uninfected cells via the binding to several surface receptors such as CD26, CXCR4, heparan sulfate proteoglycans (HSPG) or LDLR. Neurons are rarely infected, but they internalize Tat via their LDLR. Endosomal low pH allows Tat to cross the endosome membrane to enter the cytosol and eventually further translocate into the nucleus, thereby inducing severe celldysfunctions ranging from cell activation to cell death. Through its interaction with nuclear HATs, Tat is potentially able to control the acetylation-dependent cellular gene expression. Tat seems toinhibit the HAT activity of KAT5/Tip60 and TAF1, and consequently modify the expression of specific cellular genes. Modulates the expression of many cellular genes involved in cell survival, proliferation or in coding for cytokines (such as IL10) or cytokine receptors. May be involved in the derepression of host interleukin IL2 expression. Mediates the activation of cyclin- dependent kinases and dysregulation of microtubule network. Tat plays a role in T-cell and neurons apoptosis. Tat induced neurotoxicity and apoptosis probably contribute to neuroAIDS. Host extracellular matrix metalloproteinase MMP1 cleaves Tat and decreases Tat's mediated neurotoxicity. Circulating Tat also acts as a chemokine-like and/or growth factor-like molecule that binds to specific receptors on the surface of the cells, affecting many cellular pathways. In the vascular system, Tat binds to ITGAV/ITGB3 and ITGA5/ITGB1 integrins dimers at the surface of endothelial cells and competes with bFGF for heparin-binding sites, leading to an excess of soluble bFGF. Binds to KDR/VEGFR-2. All these Tat-mediated effects enhance angiogenesis in Kaposi's sarcoma lesions.
• Reactome Pathway:
  Pausing and recovery of Tat-mediated HIV elongation (R-HSA-167238)
  Tat-mediated HIV elongation arrest and recovery (R-HSA-167243)
  Tat-mediated elongation of the HIV-1 transcript (R-HSA-167246)
  Interactions of Tat with host cellular proteins (R-HSA-176034)
  Formation of HIV-1 elongation complex containing HIV-1 Tat (R-HSA-167200)

Molecular Interaction Atlas (MIA) of This DTT

1 Approved Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
Penicillamine	DM40EF6	Cystinuria	5C60.2	Approved	[1]

3 Clinical Trial Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
ALX-40-4C	DMV934L	Human immunodeficiency virus infection	1C62	Phase 2	[2]
Ro-24-7429	DMA2UYE	Human immunodeficiency virus infection	1C62	Phase 2	[3]
Anti-HIV ribozyme therapy	DMQZJ3B	Human immunodeficiency virus infection	1C62	Phase 1/2	[4]

1 Discontinued Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
EM-2487	DMG9R8E	Human immunodeficiency virus infection	1C62	Terminated	[5]

2 Investigative Drug(s) Targeting This DTT

Drug Name	Drug ID	Indication	ICD 11	Highest Status	REF
CGP 40336A	DMEA5BZ	Discovery agent	N.A.	Investigative	[6]
Durhamycin A	DM29PTO	Discovery agent	N.A.	Investigative	[7]

References

• [1] Docking studies reveal a selective binding of D-penicillamine to the transactivator protein of human immunodeficiency virus type 1. FEBS Lett. 2002 Apr 10;516(1-3):43-6.
• [2] Anti-human immunodeficiency virus type 1 activity of an oligocationic compound mediated via gp120 V3 interactions. J Virol. 1996 May;70(5):2825-31.
• [3] A randomized trial of the activity and safety of Ro 24-7429 (Tat antagonist) versus nucleoside for human immunodeficiency virus infection. The AIDS Clinical Trials Group 213 Team. J Infect Dis. 1995 Nov;172(5):1246-52.
• [4] Clinical gene therapy research utilizing ribozymes: application to the treatment of HIV/AIDS. Methods Mol Biol. 2004;252:581-98.
• [5] EM2487, a novel anti-HIV-1 antibiotic, produced by Streptomyces sp. Mer-2487: taxonomy, fermentation, biological properties, isolation and structure elucidation. J Antibiot (Tokyo). 1999 Nov;52(11):971-82.
• [6] RNA as a target for small molecules. Curr Opin Chem Biol. 2000 Dec;4(6):678-86.
• [7] Durhamycin A, a potent inhibitor of HIV Tat transactivation. J Nat Prod. 2002 Aug;65(8):1091-5.