Nuclear factor kappa B: a potential target for anti-HIV chemotherapy.
The Nuclear Factor Kappa B (NF-kappaB) is a lymphoid-specific transcription factor, which is sequestered in the cytoplasm by the protein IkappaB. NF-kappaB plays a major role in the regulation of HIV-1 gene expression. Upon activation, NF-kappaB is released from IkappaB, moves to the nucleus, and binds to its sites on the HIV long terminal repeat to start transcription of integrated HIV genome. The present review focuses on the NF-kappaB as a potential target for the development of chemotherapy against HIV-1. Beginning from the viral-binding to reverse transcription, integration, and gene expression, to the virion maturation, the life cycle of HIV presents drug-targets at all the stages. As a result, many drugs have been developed and have entered clinical trials. Some of the most important of these are reverse transcriptase and protease inhibitors, which have been used mostly in clinical studies in the form of combined therapy. But, this combined therapy has presented the problem of resistance, due to mutations in the virus. However, targeting NF-kappaB for the suppression of virus does not present the problem of resistance, as NF-kappaB is a normal part of the human T-4 cell, and is not subject to mutations, as is the virus. An overview of the NF-kappaB system and its role in HIV-1 is presented, followed by a critical review of its current and potential synthetic inhibitors. The drugs studied against NF-kappaB fall mainly into three categories: (1) Antioxidants, against oxidative stress conditions, which aid in NF-kappaB activation, (2) IkappaB phosphorylation and degradation inhibitors (the phosphorylation and degradation of IkappaB is necessary to make NF-kappaB free and move to the nucleus), and (3) NF-kappaB DNA binding inhibitors. The antioxidants include N-Acetyl-L-cysteine (NAC), alpha-Lipoic acid, glutathione monoester, pyrrolidine dithiocarbamate, and tepoxalin, of which NAC is the best studied. The IkappaB phosphorylation and degradation inhibitors, which have been studied in the context of HIV-1 include the salicylates (sodium salicylate, and acetylsalicylic acid (aspirin)). Finally, the NF-kappaB DNA binding inhibitors, which have received attention only recently, are reviewed. These include the most potential, aurine tricarboxylic acid (ATA), a chelating agent, which has been found to inhibit NF-kappaB DNA binding at a low concentration of 30 micro M. The probable mechanism of action of these drugs is discussed alongwith relevant suggestions and conclusions.
Pande
V
V
CEQUP/Departamento de Química, Faculdade de Ciências, Universidade do Porto, Rua do Campo Alegre 687, 4169-007 Porto, Portugal.
Ramos
M J
MJ
D019380:Anti-HIV Agents / Q000378:metabolism* / Q000494:pharmacology*; D000975:Antioxidants / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000494:pharmacology; D015497:HIV-1 / Q000187:drug effects*; D006801:Humans; D051550:I-kappa B Kinase; D008958:Models, Molecular; D016328:NF-kappa B / Q000037:antagonists & inhibitors* / Q000378:metabolism*; D009687:Nuclear Proteins / Q000037:antagonists & inhibitors / Q000378:metabolism; D017346:Protein Serine-Threonine Kinases / Q000037:antagonists & inhibitors / Q000378:metabolism; D012459:Salicylates / Q000494:pharmacology
D019380:Anti-HIV Agents; D000975:Antioxidants; D004268:DNA-Binding Proteins; D004791:Enzyme Inhibitors; D016328:NF-kappa B; D009687:Nuclear Proteins; D012459:Salicylates; D017346:Protein Serine-Threonine Kinases; C496559:CHUK protein, human; D051550:I-kappa B Kinase; C496560:IKBKB protein, human; C496565:IKBKE protein, human