Abstract
HIV-1 transcription is activated by HIV-1 Tat protein, which recruits CDK9/cyclin T1 and other host transcriptional co-activators to the HIV-1 promoter. Tat itself is phosphorylated by cyclin-dependent kinase 2 (CDK2) and inhibition of CDK2 by siRNA or the iron chelators, 311 or ICL670, inhibits HIV-1 transcription. Here we have analyzed a group of novel di-2-pyridylketone thiosemicarbazone (DpT) and 2-benzoylpyridine thiosemicarbazone (BpT)-based iron chelators that exhibit marked anti-cancer activity in vitro and in vivo (Whitnall M, Howard J, Ponka P and Richardson DR (2006) Proc Natl Acad Sci USA 103:7670-5; Kalinowski DS, Yu Y, Sharpe PS, Islam M, Liao Y-T, Lovejoy DB, Kumar N, Bernhardt PV and Richardson DR. (2007) J Med Chem 50:3716-29). Several of these iron chelators, in particular Bp4aT and Bp4eT, inhibited HIV-1 transcription and replication at much lower concentrations than 311 and ICL670. Both Bp4aT and Bp4eT were not toxic after a 24 h incubation. However, longer incubations for 48 h or 72 h resulted in cytotoxicity. Analysis of the molecular mechanism of HIV-1 inhibition showed that the novel iron chelators inhibited basal HIV-1 transcription, but not the NF-κB-dependent transcription or transcription from a HIV-1 promoter with inactivated SP1 sites. The chelators inhibited the activities of CDK2 and cyclin-dependent kinase 9 (CDK9)/cyclin T1, suggesting that inhibition of CDK9 may contribute to the inhibition of HIV-1 transcription. Our study suggests the potential usefulness of Bp4aT or Bp4eT in anti-retroviral regimens, particularly where resistance to standard treatment occurs.
- Received September 26, 2010.
- Revision received October 7, 2010.
- Accepted October 18, 2010.
- The American Society for Pharmacology and Experimental Therapeutics