| Autor: |
Marfurt, Jutta, Chalfein, Ferryanto, Prayoga, Pak, Wabiser, Frans, Kenangalem, Enny, Piera, Kim A., Fairlie, David P., Tjitra, Emiliana, Anstey, Nicholas M., Andrews, Kathy T., Price, Ric N. |
| Zdroj: |
Antimicrobial Agents and Chemotherapy; December 2010, Vol. 55 Issue: 3 p961-966, 6p |
| Abstrakt: |
ABSTRACTHistone acetylation plays an important role in regulating gene transcription and silencing in Plasmodium falciparum. Histone deacetylase (HDAC) inhibitors, particularly those of the hydroxamate class, have been shown to have potent in vitroactivity against drug-resistant and -sensitive laboratory strains of P. falciparum, raising their potential as a new class of antimalarial compounds. In the current study, stage-specific ex vivosusceptibility profiles of representative hydroxamate-based HDAC inhibitors suberoylanilide hydroxamic acid (SAHA), 2-ASA-9, and 2-ASA-14 (2-ASA-9 and 2-ASA-14 are 2-aminosuberic acid-based HDAC inhibitors) were assessed in multidrug-resistant clinical isolates of P. falciparum(n= 24) and P. vivax(n= 25) from Papua, Indonesia, using a modified schizont maturation assay. Submicromolar concentrations of SAHA, 2-ASA-9, and 2-ASA-14 inhibited the growth of both P. falciparum(median 50% inhibitory concentrations [IC50s] of 310, 533, and 266 nM) and P. vivax(median IC50s of 170, 503, and 278 nM). Inverse correlation patterns between HDAC inhibitors and chloroquine for P. falciparumand mefloquine for P. vivaxindicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivoagainst P. vivaxschizont maturation, comparable to that in P. falciparum, suggesting that HDAC inhibitors may be promising candidates for antimalarial therapy in geographical locations where both species are endemic. Further studies optimizing the selectivity and in vivoefficacy of HDAC inhibitors in Plasmodiumspp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy. |
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