Novel inhibitor of Plasmodium histone deacetylase that cures P. berghei-infected mice.
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.
Agbor-Enoh
S
S
Department of Biochemistry and Molecular Biology, Georgetown University Medical Center, Washington, DC 20057, USA.
Seudieu
C
C
Davidson
E
E
Dritschilo
A
A
Jung
M
M
D000818:Animals; D000962:Antimalarials / Q000494:pharmacology / Q000627:therapeutic use; D004791:Enzyme Inhibitors / Q000494:pharmacology / Q000627:therapeutic use; D006367:HeLa Cells; D056572:Histone Deacetylase Inhibitors; D006801:Humans; D008288:Malaria / Q000188:drug therapy* / Q000469:parasitology; D051379:Mice; D008813:Mice, Inbred ICR; D021261:Parasitic Sensitivity Tests; D010962:Plasmodium berghei / Q000187:drug effects* / Q000201:enzymology; D010963:Plasmodium falciparum / Q000187:drug effects* / Q000201:enzymology / Q000254:growth & development; D016896:Treatment Outcome
D000962:Antimalarials; D004791:Enzyme Inhibitors; D056572:Histone Deacetylase Inhibitors