Compounds that force Plasmodium falciparum to produce its own inhibitors

项目总结/摘要 虽然疟疾可以治愈，但它是一个持续的全球健康危机，每年有2亿多使人衰弱的病例。 50万人死亡，其中大多数是五岁以下的儿童。恶性疟原虫（Plasmodium falciparum，Pf） 对所有抗疟药物，包括主要的青蒿素（ART）的耐药性。ART及其半合成 类似物被认为是治疗疟疾所必需的。抗逆转录病毒疗法在东南部广泛存在 亚洲和非洲的抗逆转录病毒药物耐药性报告越来越多。联合治疗是一种支柱 用于治疗肺结核、癌症、艾滋病和疟疾。尽管这一组合取得了巨大的成功 治疗，其有效性可能会脱轨，因为两种药物的组合可能成为事实上的 在某些不可避免的情况下进行单药治疗。此外，Pf长期暴露于ART诱导 多药耐药性我们最近发现，Pf蛋白酶体特异性抑制剂（Pf20S）可以杀死Pf， 在其生命周期的每个阶段，与抗逆转录病毒疗法协同作用，克服抗逆转录病毒疗法的耐药性。在本提案中，我们 假设我们称之为青蒿素（ATZ）--ART类似物和Pf20S的共价杂交物 抑制剂-可以增强ART的作用，并最大限度地减少对两种成分的耐药性的出现。我们 预测Pf将激活ATZ的ART组分，其与ART本身一样将与Pf蛋白结合; Pf20S将产生ATZ修饰的寡肽;并且肽与Pf20S的延长接触 活性位点将增加ATZ的Pf20S抑制剂组分的结合，并克服 可能由Pf20S点突变引起的结合减少。与此相一致，我们有 合成的ATZ是比其组分Pf20S抑制剂更有效的Pf20S抑制剂，和 这些ATZ对野生型、Pf20S耐药和ART耐药K13 Pf3是有效的。 目的探讨AZT的作用机制，开发更多长效的类药AZT。 在靶标上的停留时间，以便在寄生虫离开其生命周期的阶段时杀死寄生虫， 对抗逆转录病毒疗法有内在抵抗力

Project Summary/Abstract Though curable, malaria is a persistent global health crisis, with over 200 million debilitating cases a year and half a million deaths, mostly in children under five. Plasmodium falciparum (Pf) has developed resistance to all antimalarials, including the mainstay artemisinins (ARTs). ART and its semi-synthetic analogs are considered essential for malaria treatment. ART resistance is widespread in Southeast Asia and there are increasing reports of ART resistance in Africa. Combination therapy is a backbone for treatment of tuberculosis, cancer, HIV and malaria. Despite the huge success of the combination therapy, its efficaciousness can be derailed as a two-drug combination can become de facto monotherapy under certain unavoidable situations. Moreover, extended exposure of Pf to ART induces multidrug tolerance. We recently showed that inhibitors specific for Pf proteasome (Pf20S) can kill Pf in each stage of its life cycle and synergize with ART, overcoming ART resistance. In this proposal, we hypothesize that what we call an artezomib (ATZ) – a covalent hybrid of an ART analogue and a Pf20S inhibitor – can enhance ART action and minimize the emergence of resistance to both components. We predict that Pf will active the ART component of ATZ, which, like ART itself, will bind to Pf proteins; Pf20S will generate ATZ-modified oligopeptides; and the peptides' extended contact with the Pf20S active site will augment the binding of the Pf20S inhibitor component of ATZ and overcome the decreased binding that might result from Pf20S point mutations. Consistent with this, we have synthesized ATZs that are more potent Pf20S inhibitors than their component Pf20S inhibitor, and these ATZs are potent against wild type, Pf20S inhibitor-resistant and ART-resistant K13 Pf. We now aim to explore the mechanism of action of AZTs and develop more drug-like AZTs with a long residence time on target so as to kill parasites when they exit the stage of their life cycle in which they are intrinsically resistant to ARTs.