Compounds that force Plasmodium falciparum to produce its own inhibitors

项目摘要/摘要 虽然疟疾是可以治愈的，但它是一种持续的全球健康危机，每年有超过2亿例使人衰弱的病例。 150万人死亡，其中大部分是五岁以下的儿童。恶性疟原虫(PF)已发展成 对所有抗疟疾药物，包括主要的青蒿素类药物(ARTS)具有抗药性。艺术及其半合成 类似物被认为是疟疾治疗所必需的。艺术抵抗在东南部普遍存在 亚洲和非洲有越来越多的抗逆转录病毒药物的报道。联合疗法是治疗的主心骨 用于治疗结核病、癌症、艾滋病毒和疟疾。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 在某些不可避免的情况下进行单一治疗。此外，长期接触抗逆转录病毒药物会导致 多药耐受。我们最近发现针对Pf蛋白酶体的抑制剂(Pf20S)可以杀死Pf。 其生命周期的每个阶段与ART协同作用，克服ART阻力。在这项提案中，我们 假设我们所说的artezomib(ATZ)-ART类似物和Pf20S的共价杂交 抑制剂-可以增强抗逆转录病毒治疗的作用，并最大限度地减少对这两种成分的耐药性。我们 预测Pf将激活ATZ的ART成分，与ART本身一样，它将与Pf蛋白结合； Pf20S将产生ATZ修饰的寡肽；这些肽与Pf20S的接触范围更广 活性部位将增强ATZ的Pf20S抑制剂成分的结合，并克服 Pf20S点突变可能导致的结合减少。与此一致的是，我们有 合成的ATZ是比其组成的Pf20S抑制剂更有效的Pf20S抑制剂，以及 这些ATZ对野生型、抗Pf20S抑制剂和抗ART的K13PF具有很强的抗药性。我们现在 目的探讨AZTS的作用机制，开发更多具有长寿命的类药物AZT。 在目标上的停留时间，以便在寄生虫离开其生命周期的阶段时杀死它们 从本质上来说就是对艺术的抵触。

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.