Eskitis Institute for Cell and Molecular Therapies, Griffith University, Brisbane, Queensland, Australia.
Antimicrob Agents Chemother. 2012 Jul;56(7):3849-56. doi: 10.1128/AAC.00030-12. Epub 2012 Apr 16.
Histone deacetylase (HDAC) enzymes posttranslationally modify lysines on histone and nonhistone proteins and play crucial roles in epigenetic regulation and other important cellular processes. HDAC inhibitors (e.g., suberoylanilide hydroxamic acid [SAHA; also known as vorinostat]) are used clinically to treat some cancers and are under investigation for use against many other diseases. Development of new HDAC inhibitors for noncancer indications has the potential to be accelerated by piggybacking onto cancer studies, as several HDAC inhibitors have undergone or are undergoing clinical trials. One such compound, SB939, is a new orally active hydroxamate-based HDAC inhibitor with an improved pharmacokinetic profile compared to that of SAHA. In this study, the in vitro and in vivo antiplasmodial activities of SB939 were investigated. SB939 was found to be a potent inhibitor of the growth of Plasmodium falciparum asexual-stage parasites in vitro (50% inhibitory concentration [IC(50)], 100 to 200 nM), causing hyperacetylation of parasite histone and nonhistone proteins. In combination with the aspartic protease inhibitor lopinavir, SB939 displayed additive activity. SB939 also potently inhibited the in vitro growth of exoerythrocytic-stage Plasmodium parasites in liver cells (IC(50), ~150 nM), suggesting that inhibitor targeting to multiple malaria parasite life cycle stages may be possible. In an experimental in vivo murine model of cerebral malaria, orally administered SB939 significantly inhibited P. berghei ANKA parasite growth, preventing development of cerebral malaria-like symptoms. These results identify SB939 as a potent new antimalarial HDAC inhibitor and underscore the potential of investigating next-generation anticancer HDAC inhibitors as prospective new drug leads for treatment of malaria.
组蛋白去乙酰化酶 (HDAC) 酶在翻译后修饰组蛋白和非组蛋白蛋白上的赖氨酸，并在表观遗传调控和其他重要细胞过程中发挥关键作用。HDAC 抑制剂（例如，琥珀酰亚胺基羟肟酸[SAHA；也称为伏立诺他]）临床上用于治疗某些癌症，并正在研究用于治疗许多其他疾病。为非癌症适应症开发新的 HDAC 抑制剂有可能通过利用癌症研究来加速，因为几种 HDAC 抑制剂已经或正在进行临床试验。一种这样的化合物，SB939，是一种新型的口服活性羟肟酸基 HDAC 抑制剂，与 SAHA 相比具有改善的药代动力学特征。在这项研究中，研究了 SB939 的体外和体内抗疟原虫活性。发现 SB939 是体外生长的恶性疟原虫无性期寄生虫的有效抑制剂（50%抑制浓度[IC（50）]，100 至 200 nM），导致寄生虫组蛋白和非组蛋白蛋白的过度乙酰化。与天冬氨酸蛋白酶抑制剂洛匹那韦联合使用时，SB939 表现出相加活性。SB939 还能有效抑制肝脏细胞中体外红细胞外期疟原虫的生长（IC（50），~150 nM），这表明可能针对疟疾寄生虫多个生命周期阶段的抑制剂靶向作用是可能的。在实验性脑型疟疾的体内小鼠模型中，口服给予 SB939 可显著抑制 P. berghei ANKA 寄生虫的生长，防止出现类似脑型疟疾的症状。这些结果表明 SB939 是一种有效的新型抗疟 HDAC 抑制剂，并强调了研究下一代抗癌 HDAC 抑制剂作为治疗疟疾的潜在新型药物先导物的潜力。
