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首页> 外文期刊>Antimicrobial agents and chemotherapy. >Potent antimalarial activity of histone deacetylase inhibitor analogues.
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Potent antimalarial activity of histone deacetylase inhibitor analogues.

机译：组蛋白脱乙酰基酶抑制剂类似物的强抗疟活性。

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摘要

The malaria parasite Plasmodium falciparum has at least five putative histone deacetylase (HDAC) enzymes, which have been proposed as new antimalarial drug targets and may play roles in regulating gene transcription, like the better-known and more intensively studied human HDACs (hHDACs). Fourteen new compounds derived from l-cysteine or 2-aminosuberic acid were designed to inhibit P. falciparum HDAC-1 (PfHDAC-1) based on homology modeling with human class I and class II HDAC enzymes. The compounds displayed highly potent antiproliferative activity against drug-resistant (Dd2) or drug sensitive (3D7) strains of P. falciparum in vitro (50% inhibitory concentration of 13 to 334 nM). Unlike known hHDAC inhibitors, some of these new compounds were significantly more toxic to P. falciparum parasites than to mammalian cells. The compounds inhibited P. falciparum growth in erythrocytes at both the early and late stages of the parasite's life cycle and caused altered histone acetylation patterns (hyperacetylation), which is a marker of HDAC inhibition in mammalian cells. These results support PfHDAC enzymes as being promising targets for new antimalarial drugs.
机译：疟原虫恶性疟原虫具有至少五个推定的组蛋白脱乙酰基酶（HDAC）酶，这些酶已被提议作为抗疟药的新靶标，并且可能在调节基因转录中发挥作用，例如更著名和研究更多的人类HDAC（hHDAC）。基于与人类I类和II类HDAC酶的同源性模型，设计了14种衍生自L-半胱氨酸或2-氨基磺酸的化合物来抑制恶性疟原虫HDAC-1（PfHDAC-1）。该化合物在体外对恶性疟原虫的耐药菌株（Dd2）或药物敏感菌株（3D7）表现出高度有效的抗增殖活性（50％抑制浓度为13至334 nM）。与已知的hHDAC抑制剂不同，这些新化合物中的一些对恶性疟原虫的毒性比对哺乳动物细胞的毒性大得多。该化合物在寄生虫生命周期的早期和晚期都抑制红细胞中恶性疟原虫的生长，并导致改变的组蛋白乙酰化模式（超乙酰化），这是哺乳动物细胞中HDAC抑制的标志。这些结果支持PfHDAC酶成为新的抗疟药的有希望的靶标。

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