抗疟原苯并异噻唑酮的分子机制：疟原虫属物种的物种选择性抑制剂。MEP途径酶，IspD。,Scientific Reports

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抗疟原苯并异噻唑酮的分子机制：疟原虫属物种的物种选择性抑制剂。MEP途径酶，IspD。
Scientific Reports ( IF 3.8 ) Pub Date : 2016-11-18 , DOI: 10.1038/srep36777
Kathryn E. Price , Christopher M. Armstrong , Leah S. Imlay , Dana M. Hodge , C. Pidathala , Natalie J. Roberts , Jooyoung Park , Marwa Mikati , Raman Sharma , Alexandre S. Lawrenson , Niraj H. Tolia , Neil G. Berry , Paul M. O’Neill , Audrey R. Odom John

磷酸甲基赤藓糖醇（MEP）途径是在疟原虫中发现的一种重要的代谢途径，但在哺乳动物中却不存在，这使其成为发现新型和选择性抗疟疾疗法的极具吸引力的靶标。使用高通量筛选，我们已经确定2-苯基苯并[d]异噻唑-3（2H）-是疟原虫属物种的物种选择性抑制剂。MEP途径的第三种催化酶2-C-甲基_-D-赤藓糖醇-4-磷酸胞苷基转移酶（IspD）。具有EC _50的2-苯基苯并[d]异噻唑-3（2H）-酮对恶性疟原虫和间日疟原虫IspD表现出纳摩尔抑制活性并阻止恶性疟原虫的生长。低于400 nM的值。在计算机模拟中，连同酶，遗传和晶体学研究，已经建立了一种作用机理，包括在IspD结合位点对抑制剂进行初始非共价识别，然后通过攻击活性位点上的半胱氨酸残基形成二硫键。苯并[d]异噻唑-3（2H）-一芯。这些小分子对疟原虫属物种的物种选择性抑制活性。IspD和培养的寄生虫表明它们有潜力作为追求新型药物治疗疟疾的先导化合物。

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Molecular Mechanism of Action of Antimalarial Benzoisothiazolones: Species-Selective Inhibitors of the Plasmodium spp. MEP Pathway enzyme, IspD.

The methylerythritol phosphate (MEP) pathway is an essential metabolic pathway found in malaria parasites, but absent in mammals, making it a highly attractive target for the discovery of novel and selective antimalarial therapies. Using high-throughput screening, we have identified 2-phenyl benzo[d]isothiazol-3(2H)-ones as species-selective inhibitors of Plasmodium spp. 2-C-methyl-_D-erythritol-4-phosphate cytidyltransferase (IspD), the third catalytic enzyme of the MEP pathway. 2-Phenyl benzo[d]isothiazol-3(2H)-ones display nanomolar inhibitory activity against P. falciparum and P. vivax IspD and prevent the growth of P. falciparum in culture, with EC₅₀ values below 400 nM. In silico modeling, along with enzymatic, genetic and crystallographic studies, have established a mechanism-of-action involving initial non-covalent recognition of inhibitors at the IspD binding site, followed by disulfide bond formation through attack of an active site cysteine residue on the benzo[d]isothiazol-3(2H)-one core. The species-selective inhibitory activity of these small molecules against Plasmodium spp. IspD and cultured parasites suggests they have potential as lead compounds in the pursuit of novel drugs to treat malaria.

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