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.
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.
Center for Sickle Cell Disease, Department of Medicine, Howard University, Washington DC 20001, USA.
Zufan
Z
Debebe
Tatyana
T
Ammosova
Denitra
D
Breuer
David B
DB
Lovejoy
Danuta S
DS
Kalinowski
Krishna
K
Kumar
Marina
M
Jerebtsova
Patricio
P
Ray
Fatah
F
Kashanchi
Victor R
VR
Gordeuk
Des R
DR
Richardson
Sergei
S
Nekhai
D002478:Cells, Cultured; D051357:Cyclin-Dependent Kinase 2 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D042863:Cyclin-Dependent Kinase 9 / Q000037:antagonists & inhibitors* / Q000378:metabolism; D057809:HEK293 Cells; D015497:HIV-1 / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007501:Iron / Q000037:antagonists & inhibitors / Q000378:metabolism; D007502:Iron Chelating Agents / Q000737:chemistry / Q000494:pharmacology*; D013882:Thiosemicarbazones / Q000737:chemistry / Q000494:pharmacology*; D014158:Transcription, Genetic / Q000187:drug effects / Q000502:physiology
C550921:2-benzoylpyridine 4-ethyl-3-thiosemicarbazone; D007502:Iron Chelating Agents; D013882:Thiosemicarbazones; C539263:di-2-pyridylketone-4,4-dimethyl-3-thiosemicarbazone; D007501:Iron; C495894:CDK2 protein, human; D051357:Cyclin-Dependent Kinase 2; D042863:Cyclin-Dependent Kinase 9