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Antimicrob Agents Chemother 2014 Nov;58(11):6558-71

Phenyl-1-pyridin-2yl-ethanone (PPY)-based Iron Chelators Increase IKBa Expression, Modulate CDK2 and CDK9 activities and Inhibit HIV-1 Transcription.

Kumari N, Iordanskiy S, Kovalskyy D, Breuer D, Niu X, Lin X, Xu M, Gavrilenko K, Kashanchi F, Dhawan S, Nekhai S

Abstract

HIV-1 transcription is activated by Tat protein that recruits CDK9/cyclin T1 to HIV-1 promoter. CDK9 is phosphorylated by CDK2 which facilitates formation of large molecular weight positive transcription elongation factor b (P-TEFb) complex. We 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 have tested a set of novel iron chelators for their ability to inhibit HIV-1 transcription and to elucidate their mechanism of action. Novel phenyl-1-pyridin-2yl-ethanone (PPY)-based iron chelators were synthesized and examined for their effect on the cellular iron, HIV-1 inhibition and cytotoxicity. Activities of CDK2 and CDK9, expression of CDK9-dependent and CDK2 inhibitory mRNAs, NF-¿B expression and HIV-1 and NF-¿B-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 had less effect on HIV-1 subtype C. Iron chelators upregulated the expression of IKBa with increased accumulation of cytoplasmic NF-¿B. The iron chelators inhibited CDK2 activity, and reduced 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 affecting equally HIV-1, Sp1, or NF-kB-driven transcription. By virtue of their involvement in targeting several key steps in the HIV-1 transcription, these novel iron chelators have the potential for the development of new therapeutics for the treatment of HIV-1 infection.


Category: Journal Article
PubMed ID: #25155598 DOI: 10.1128/AAC.02918-14
Includes FDA Authors from Scientific Area(s): Biologics
Entry Created: 2014-01-06 Entry Last Modified: 2014-12-07
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