Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages.
Discovery of HDAC inhibitors with potent activity against multiple malaria parasite life cycle stages.
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DOI：
10.1016/j.ejmech.2014.05.050
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发表时间：
2014-07-23
影响因子：
6.7
通讯作者：
Kurz T
中科院分区：
文献类型：
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作者：
Hansen FK;Sumanadasa SD;Stenzel K;Duffy S;Meister S;Marek L;Schmetter R;Kuna K;Hamacher A;Mordmüller B;Kassack MU;Winzeler EA;Avery VM;Andrews KT;Kurz T
在这项工作中，我们研究了一系列含有烷氧基酰胺连接单元接头区域的 HDAC 抑制剂的抗疟原虫活性。 HDAC 抑制剂 1a (LMK235) 先前被证明是人类 HDAC4 和 5 的新型特异性抑制剂，被用作使用简单的固相支持合成快速构建 HDAC 抑制剂小型文库的起点。这些新型 HDAC 抑制剂中的几种被发现对无性阶段恶性疟原虫疟原虫具有有效的体外活性。代表性化合物能够使恶性疟原虫组蛋白高度乙酰化，并抑制重组 PfHDAC1 和恶性疟原虫核提取物的脱乙酰酶活性。还在体外筛选所有化合物针对伯氏疟原虫红细胞外阶段的活性，并进一步测试所选化合物针对晚期（IV 和 V）恶性疟原虫配子细胞的活性。值得注意的是，一些化合物对测试的所有三个生命周期阶段（无性、红细胞外和配子细胞阶段）均表现出纳摩尔活性，并且与参考 HDAC 抑制剂辛二酰苯胺异羟肟酸 (SAHA) 相比，一些化合物显示出显着增加的寄生虫选择性。这些数据表明，开发针对多个疟疾寄生虫生命周期阶段的 HDAC 抑制剂是可能的。
In this work we investigated the antiplasmodial activity of a series of HDAC inhibitors containing an alkoxyamide connecting-unit linker region. HDAC inhibitor 1a (LMK235), previously shown to be a novel and specific inhibitor of human HDAC4 and 5, was used as a starting point to rapidly construct a mini-library of HDAC inhibitors using a straightforward solid-phase supported synthesis. Several of these novel HDAC inhibitors were found to have potent in vitro activity against asexual stage P. falciparum malaria parasites. Representative compounds were shown to hyperacetylate P. falciparum histones and to inhibit deacetylase activity of recombinant PfHDAC1 and P. falciparum nuclear extracts. All compounds were also screened in vitro for activity against P. berghei exo-erythrocytic stages and selected compounds were further tested against late stage (IV and V) P. falciparum gametocytes. Of note, some compounds showed nanomolar activity against all three life cycle stages tested (asexual, exo-erythrocytic and gametocyte stages) and several compounds displayed significantly increased parasite selectivity compared to the reference HDAC inhibitor suberoylanilide hydroxamic acid (SAHA). These data suggest that it may be possible to develop HDAC inhibitors that target multiple malaria parasite life cycle stages.