PT  - JOURNAL ARTICLE
AU  - Zufan Debebe
AU  - Tatyana Ammosova
AU  - Denitra Breuer
AU  - David B. Lovejoy
AU  - Danuta S. Kalinowski
AU  - Pradeep K. Karla
AU  - Krishna Kumar
AU  - Marina Jerebtsova
AU  - Patricio Ray
AU  - Fatah Kashanchi
AU  - Victor R. Gordeuk
AU  - Des R. Richardson
AU  - Sergei Nekhai
TI  - Iron Chelators of the Di-2-pyridylketone Thiosemicarbazone and 2-Benzoylpyridine Thiosemicarbazone Series Inhibit HIV-1 Transcription: Identification of Novel Cellular Targets—Iron, Cyclin-Dependent Kinase (CDK) 2, and CDK9
AID  - 10.1124/mol.110.069062
DP  - 2011 Jan 01
TA  - Molecular Pharmacology
PG  - 185--196
VI  - 79
IP  - 1
4099  - http://molpharm.aspetjournals.org/content/79/1/185.short
4100  - http://molpharm.aspetjournals.org/content/79/1/185.full
SO  - Mol Pharmacol2011 Jan 01; 79
AB  - HIV-1 transcription is activated by HIV-1 Tat protein, which recruits cyclin-dependent kinase 9 (CDK9)/cyclin T1 and other host transcriptional coactivators to the HIV-1 promoter. Tat itself is phosphorylated by CDK2, and inhibition of CDK2 by small interfering RNA, the iron chelator 2-hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311), and the iron chelator deferasirox (ICL670) inhibits HIV-1 transcription. Here we have analyzed a group of novel di-2-pyridylketone thiosemicarbazone- and 2-benzoylpyridine thiosemicarbazone-based iron chelators that exhibit marked anticancer activity in vitro and in vivo (Proc Natl Acad Sci USA 103:7670–7675, 2006; J Med Chem 50:3716–3729, 2007). Several of these iron chelators, in particular 2-benzoylpyridine 4-allyl-3-thiosemicarbazone (Bp4aT) and 2-benzoylpyridine 4-ethyl-3-thiosemicarbazone (Bp4eT), inhibited HIV-1 transcription and replication at much lower concentrations than did 311 and ICL670. Neither Bp4aT nor Bp4eT were 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 nuclear factor-κB-dependent transcription or transcription from an HIV-1 promoter with inactivated SP1 sites. The chelators inhibited the activities of CDK2 and 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 antiretroviral regimens, particularly where resistance to standard treatment occurs.