Inhibitors of HIV-1 Tat-mediated transactivation.
The transactivation responsive (TAR) RNA is the 5'-leader sequence of the HIV-1 mRNA genome and interacts with the Tat protein during transcription. Tat and the positive transcription elongation factor (P-TEFb) complex bind to TAR to promote efficient transcription of the full-length HIV genome. In the absence of the TAR.Tat.P-TEFb interaction, viral transcription is inefficient, which makes this RNA-protein complex an important target for therapeutic intervention of HIV replication. Inhibitors of HIV-1 transactivation mainly target: 1) TAR RNA, 2) Tat protein and 3) Tat.P-TEFb complex. 1) Compounds against TAR RNA are the most numerous: besides cationic peptides, which were initially developed, recent advances in TAR binding inhibitors include oligonucleotide based-agents and small molecules. Specific research efforts are currently underway to increase cellular uptake. 2) By targeting the Tat protein, both transactivation and other Tat-mediated intra/extracellular functions are affected. Various biopolymeric drugs are reported to effectively inhibit Tat activity. In addition, Tat-targeted antibodies have recently been developed. 3) Intracellular proteins have been discovered to disrupt Tat.P-TEFb interaction, raising the chance of inhibiting HIV-1 transcription via novel mechanisms.
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Department of Histology, Microbiology and Medical Biotechnologies, University of Padua, via Gabelli 63, 35123 Padua, Italy. sara.richter@unipd.it
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D019380:Anti-HIV Agents / Q000737:chemistry / Q000494:pharmacology*; D015696:Gene Products, tat / Q000037:antagonists & inhibitors* / Q000378:metabolism; D016325:HIV Long Terminal Repeat; D015497:HIV-1; D006801:Humans; D015394:Molecular Structure; D042925:Positive Transcriptional Elongation Factor B / Q000037:antagonists & inhibitors / Q000378:metabolism; D012367:RNA, Viral / Q000037:antagonists & inhibitors / Q000378:metabolism; D015533:Transcriptional Activation; D054322:tat Gene Products, Human Immunodeficiency Virus
D019380:Anti-HIV Agents; D015696:Gene Products, tat; D012367:RNA, Viral; D054322:tat Gene Products, Human Immunodeficiency Virus; D042925:Positive Transcriptional Elongation Factor B