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Antimicrobial Agents and Chemotherapy, May 2009, p. 1727-1734, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.00729-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.

Novel Inhibitor of Plasmodium Histone Deacetylase That Cures P. berghei-Infected Mice{triangledown}

S. Agbor-Enoh,1,4 C. Seudieu,1 E. Davidson,1 A. Dritschilo,2,3 and M. Jung2*

Departments of Biochemistry and Molecular Biology,1 Radiation Medicine,2 Oncology, Georgetown University Medical Center, Vincent T. Lombardi Comprehensive Cancer Center, Washington, DC 20057,3 Biotechnology Center, University of Yaounde I, Nkol-Bisong, Yaounde, Cameroon4

Received 3 June 2008/ Returned for modification 10 August 2008/ Accepted 4 February 2009

Histone deacetylases (HDAC) are potential targets for the development of new antimalarial drugs. The growth of Plasmodium falciparum and other apicomplexans can be suppressed in the presence of potent HDAC inhibitors in vitro and in vivo; however, in vivo parasite suppression is generally incomplete or reversible after the discontinuation of drug treatment. Furthermore, most established HDAC inhibitors concurrently show broad toxicities against parasites and human cells and high drug concentrations are required for effective antimalarial activity. Here, we report on HDAC inhibitors that are potent against P. falciparum at subnanomolar concentrations and that have high selectivities; the lead compounds have mean 50% inhibitory concentrations for the killing of the malaria parasite up to 950 times lower than those for the killing of mammalian cells. These potential drugs improved survival and completely and irreversibly suppressed parasitemia in P. berghei-infected mice.

* Corresponding author. Mailing address: Department of Radiation Medicine, Georgetown University Medical Center, Research Building, Room E211, Box 571482, 3970 Reservoir Rd., NW, Washington, DC 20057-1482. Phone: (202) 687-8352. Fax: (202) 687-0400. E-mail: jungm{at}georgetown.edu

{triangledown} Published ahead of print on 17 February 2009.

Antimicrobial Agents and Chemotherapy, May 2009, p. 1727-1734, Vol. 53, No. 5
0066-4804/09/$08.00+0     doi:10.1128/AAC.00729-08
Copyright © 2009, American Society for Microbiology. All Rights Reserved.





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