Phenyl-1-Pyridin-2yl-Ethanone-Based Iron Chelators Increase IκB-α Expression, Modulate CDK2 and CDK9 Activities, and Inhibit HIV-1 Transcription
| Autor: | Dmytro Kovalskyy, Fatah Kashanchi, Sergey Iordanskiy, Konstantin S. Gavrilenko, Sergei Nekhai, Xiaomei Niu, Subhash Dhawan, Denitra Breuer, Xionghao Lin, Namita Kumari, Min Xu |
|---|---|
| Rok vydání: | 2014 |
| Předmět: |
Cyclin-Dependent Kinase Inhibitor p21
Gene Expression Regulation Viral Cyclin T1 Cyclin E Transcription Genetic Cell Survival Transcription Factor RelA Cyclin A Iron Chelating Agents Virus Replication gag Gene Products Human Immunodeficiency Virus Antiviral Agents Cell Line Transcription (biology) medicine Humans Pharmacology (medical) RNA Messenger P-TEFb Pharmacology biology Cyclin T Cyclin-Dependent Kinase 2 Cyclin-dependent kinase 2 env Gene Products Human Immunodeficiency Virus virus diseases Reverse Transcription Cyclin-Dependent Kinase 9 Molecular biology I-kappa B Kinase HEK293 Cells Infectious Diseases Mechanism of action S Phase Cell Cycle Checkpoints HIV-1 biology.protein medicine.symptom |
| Zdroj: | Antimicrobial Agents and Chemotherapy. 58:6558-6571 |
| ISSN: | 1098-6596 0066-4804 |
| DOI: | 10.1128/aac.02918-14 |
| Popis: | HIV-1 transcription is activated by the Tat protein, which recruits CDK9/cyclin T1 to the HIV-1 promoter. CDK9 is phosphorylated by CDK2, which facilitates formation of the high-molecular-weight positive transcription elongation factor b (P-TEFb) complex. We previously showed that chelation of intracellular iron inhibits CDK2 and CDK9 activities and suppresses HIV-1 transcription, but the mechanism of the inhibition was not understood. In the present study, we tested a set of novel iron chelators for the ability to inhibit HIV-1 transcription and elucidated their mechanism of action. Novel phenyl-1-pyridin-2yl-ethanone (PPY)-based iron chelators were synthesized and examined for their effects on cellular iron, HIV-1 inhibition, and cytotoxicity. Activities of CDK2 and CDK9, expression of CDK9-dependent and CDK2-inhibitory mRNAs, NF-κB expression, and HIV-1- and NF-κB-dependent transcription were determined. PPY-based iron chelators significantly inhibited HIV-1, with minimal cytotoxicity, in cultured and primary cells chronically or acutely infected with HIV-1 subtype B, but they had less of an effect on HIV-1 subtype C. Iron chelators upregulated the expression of IκB-α, with increased accumulation of cytoplasmic NF-κB. The iron chelators inhibited CDK2 activity and reduced the amount of CDK9/cyclin T1 in the large P-TEFb complex. Iron chelators reduced HIV-1 Gag and Env mRNA synthesis but had no effect on HIV-1 reverse transcription. In addition, iron chelators moderately inhibited basal HIV-1 transcription, equally affecting HIV-1 and Sp1- or NF-κB-driven transcription. By virtue of their involvement in targeting several key steps in HIV-1 transcription, these novel iron chelators have the potential for the development of new therapeutics for the treatment of HIV-1 infection. |
| Databáze: | OpenAIRE |
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