Menzies School of Health Research, P.O. Box 41096, Casuarina, Darwin, NT 0811, Australia.
Antimicrob Agents Chemother. 2011 Mar;55(3):961-6. doi: 10.1128/AAC.01220-10. Epub 2010 Dec 6.
Histone 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 vitro activity 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 vivo susceptibility 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. falciparum and mefloquine for P. vivax indicate species-specific susceptibility profiles for HDAC inhibitors. These HDAC inhibitors were also found to be potent ex vivo against P. vivax schizont 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 vivo efficacy of HDAC inhibitors in Plasmodium spp. and defining drug interaction with common antimalarial compounds are warranted to investigate the role of HDAC inhibitors in antimalarial therapy.
组蛋白乙酰化在调节疟原虫的基因转录和沉默中起着重要作用。组蛋白去乙酰化酶（HDAC）抑制剂，特别是那些羟肟酸类抑制剂，已被证明对耐药和敏感的实验室疟原虫株具有很强的体外活性，这增加了它们作为一类新的抗疟化合物的潜力。在目前的研究中，使用改良的裂殖体成熟测定法，评估了代表羟肟酸基 HDAC 抑制剂的亚磺酰基苯胺羟肟酸（SAHA）、2-ASA-9 和 2-ASA-14（2-ASA-9 和 2-ASA-14 是 2-氨基琥珀酸基 HDAC 抑制剂）在来自印度尼西亚巴布亚的多药耐药临床分离株中的疟原虫（n=24）和间日疟原虫（n=25）中的阶段特异性体外敏感性。在体外，亚微摩尔浓度的 SAHA、2-ASA-9 和 2-ASA-14 抑制了疟原虫（疟原虫的中位数 50%抑制浓度[IC₅₀]为 310、533 和 266 nM）和间日疟原虫（间日疟原虫的中位数 IC₅₀为 170、503 和 278 nM）的生长。HDAC 抑制剂与氯喹对疟原虫和甲氟喹对间日疟原虫之间的逆相关模式表明，HDAC 抑制剂具有种特异性的敏感性特征。这些 HDAC 抑制剂对间日疟原虫裂殖体成熟也具有很强的体外活性，与疟原虫相当，这表明 HDAC 抑制剂可能是在这两种物种流行的地区进行抗疟治疗的有前途的候选药物。进一步研究优化 HDAC 抑制剂在疟原虫属中的选择性和体内疗效，并确定与常见抗疟化合物的药物相互作用，以研究 HDAC 抑制剂在抗疟治疗中的作用是必要的。
