Target Information
Target General Information | Top | |||||
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Target ID |
T93783
(Former ID: TTDS00322)
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Target Name |
Human immunodeficiency virus Tat protein (HIV tat)
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Synonyms |
Transactivating regulatory protein; TAT protein
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Gene Name |
HIV tat
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Target Type |
Successful target
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[1] | ||||
Disease | [+] 1 Target-related Diseases | + | ||||
1 | Rheumatoid arthritis [ICD-11: FA20] | |||||
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.
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BioChemical Class |
Lentiviruses Tat family
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UniProt ID | ||||||
Sequence |
MEPVDPRLEPWKHPGSQPKTACTNCYCKKCCFHCQVCFITKALGISYGRKKRRQRRRAHQ
NSQTHQASLSKQPTSQPRGDPTGPKE Click to Show/Hide
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3D Structure | Click to Show 3D Structure of This Target | PDB |
Drugs and Modes of Action | Top | |||||
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Approved Drug(s) | [+] 1 Approved Drugs | + | ||||
1 | Penicillamine | Drug Info | Approved | Rheumatoid arthritis | [2], [3] | |
Clinical Trial Drug(s) | [+] 3 Clinical Trial Drugs | + | ||||
1 | ALX-40-4C | Drug Info | Phase 2 | Human immunodeficiency virus infection | [4] | |
2 | Ro-24-7429 | Drug Info | Phase 2 | Human immunodeficiency virus infection | [5] | |
3 | Anti-HIV ribozyme therapy | Drug Info | Phase 1/2 | Human immunodeficiency virus infection | [6] | |
Discontinued Drug(s) | [+] 1 Discontinued Drugs | + | ||||
1 | EM-2487 | Drug Info | Terminated | Human immunodeficiency virus infection | [7] | |
Mode of Action | [+] 2 Modes of Action | + | ||||
Inhibitor | [+] 4 Inhibitor drugs | + | ||||
1 | Penicillamine | Drug Info | [1] | |||
2 | EM-2487 | Drug Info | [11] | |||
3 | CGP 40336A | Drug Info | [12] | |||
4 | Durhamycin A | Drug Info | [13] | |||
Modulator | [+] 3 Modulator drugs | + | ||||
1 | ALX-40-4C | Drug Info | [8] | |||
2 | Ro-24-7429 | Drug Info | [9] | |||
3 | Anti-HIV ribozyme therapy | Drug Info | [10] |
Different Human System Profiles of Target | Top |
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Human Similarity Proteins
of target is determined by comparing the sequence similarity of all human proteins with the target based on BLAST. The similarity proteins for a target are defined as the proteins with E-value < 0.005 and outside the protein families of the target.
A target that has fewer human similarity proteins outside its family is commonly regarded to possess a greater capacity to avoid undesired interactions and thus increase the possibility of finding successful drugs
(Brief Bioinform, 21: 649-662, 2020).
Human Similarity Proteins
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There is no similarity protein (E value < 0.005) for this target
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Chemical Structure based Activity Landscape of Target | Top |
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Drug Property Profile of Target | Top | |
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(1) Molecular Weight (mw) based Drug Clustering | (2) Octanol/Water Partition Coefficient (xlogp) based Drug Clustering | |
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(3) Hydrogen Bond Donor Count (hbonddonor) based Drug Clustering | (4) Hydrogen Bond Acceptor Count (hbondacc) based Drug Clustering | |
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(5) Rotatable Bond Count (rotbonds) based Drug Clustering | (6) Topological Polar Surface Area (polararea) based Drug Clustering | |
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"RO5" indicates the cutoff set by lipinski's rule of five; "D123AB" colored in GREEN denotes the no violation of any cutoff in lipinski's rule of five; "D123AB" colored in PURPLE refers to the violation of only one cutoff in lipinski's rule of five; "D123AB" colored in BLACK represents the violation of more than one cutoffs in lipinski's rule of five |
References | Top | |||||
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REF 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. | |||||
REF 2 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 7264). | |||||
REF 3 | How many modes of action should an antibiotic have Curr Opin Pharmacol. 2008 Oct;8(5):564-73. | |||||
REF 4 | URL: http://www.guidetopharmacology.org Nucleic Acids Res. 2015 Oct 12. pii: gkv1037. The IUPHAR/BPS Guide to PHARMACOLOGY in 2016: towards curated quantitative interactions between 1300 protein targets and 6000 ligands. (Ligand id: 607). | |||||
REF 5 | ClinicalTrials.gov (NCT00002314) A Study of Ro 24-7429 in Patients With HIV-Related Kaposi's Sarcoma. U.S. National Institutes of Health. | |||||
REF 6 | Phase I/II Clinical Trials Using Gene-Modified Adult Hematopoietic Stem Cells for HIV: Lessons Learnt. Stem Cells Int. 2011;2011:393698. | |||||
REF 7 | Trusted, scientifically sound profiles of drug programs, clinical trials, safety reports, and company deals, written by scientists. Springer. 2015. Adis Insight (drug id 800012852) | |||||
REF 8 | Anti-human immunodeficiency virus type 1 activity of an oligocationic compound mediated via gp120 V3 interactions. J Virol. 1996 May;70(5):2825-31. | |||||
REF 9 | 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. | |||||
REF 10 | Clinical gene therapy research utilizing ribozymes: application to the treatment of HIV/AIDS. Methods Mol Biol. 2004;252:581-98. | |||||
REF 11 | 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. | |||||
REF 12 | RNA as a target for small molecules. Curr Opin Chem Biol. 2000 Dec;4(6):678-86. | |||||
REF 13 | Durhamycin A, a potent inhibitor of HIV Tat transactivation. J Nat Prod. 2002 Aug;65(8):1091-5. |
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