iron chelators

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Debebe Z, Ammosova T, Jerebtsova M, Kurantsin-Mills J, Niu X,

S, DR, Ray PE, Gordeuk VR, Nekhai S. Iron chelators ICL670

and 311 inhibit HIV-1 transcription. Virology. 2007 Jul 12; [Epub

ahead of print]

Center for Sickle Cell Disease, University College of Medicine,

520 W. St., N.W., Washington, DC 20060, USA.

HIV-1 replication is induced by an excess of iron and iron chelation

by desferrioxamine (DFO) inhibits viral replication by reducing

proliferation of infected cells. Treatment of cells with DFO and 2-

hydroxy-1-naphthylaldehyde isonicotinoyl hydrazone (311) inhibit

expression of proteins that regulate cell-cycle progression,

including cycle-dependent kinase 2 (CDK2). Our recent studies showed

that CDK2 participates in HIV-1 transcription and viral replication

suggesting that inhibition of CDK2 by iron chelators might also

affect HIV-1 transcription. Here we evaluated the effect of a

clinically approved orally effective iron chelator,

4-[3,5-bis-(hydroxyphenyl)-1,2,4- triazol-1-yl]-benzoic acid (ICL670)

and 311 on HIV-1 transcription. Both ICL670 and 311 inhibited

Tat-induced HIV-1 transcription in CEM-T cells, 293T and HeLa cells.

Neither ICL670 nor 311 induced cytotoxicity at concentrations that

inhibited HIV-1 transcription. The chelators decreased cellular

activity of CDK2 and reduced HIV-1 Tat phosphorylation by CDK2.

Neither ICL670A or 311 decreased CDK9 protein level but significantly

reduced association of CDK9 with cyclin T1 and reduced

phosphorylation of Ser-2 residues of RNA polymerase II C- terminal

domain. In conclusion, our findings add to the evidence that iron

chelators can inhibit HIV-1 transcription by deregulating CDK2 and

CDK9. Further consideration should be given to the development of

iron chelators for future anti-retroviral therapeutics.

PMID: 17631934 [PubMed - as supplied by publisher]