Compounds that force Plasmodium falciparum to produce its own inhibitors

迫使恶性疟原虫产生自身抑制剂的化合物

• 批准号: 10037851
• 负责人: Gang Lin
• 金额: $ 21.19万
• 依托单位: WEILL MEDICAL COLL OF CORNELL UNIV
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-05-22 至 2022-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10037851
• 关键词: Active Sites; Africa; African; Antimalarials; Artemisia annua; Artemisinins; Binding; Biological Models; Cells; Cessation of life; Chemicals; Child; Clinical; Combined Modality Therapy; Development; Drug Combinations; Drug Interactions; Drug resistance; Enzyme Inhibition; Erythrocytes; Evolution; Goals; HIV; Hemin; Human; Hybrids; Lactones; Life Cycle Stages; Malaria; Malignant Neoplasms; Medication Management; Mutation; Oligopeptides; Organism; Parasites; Patient Noncompliance; Penetration; Peptides; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Point Mutation; Poison; Prevention; Prodrugs; Proteasome Inhibitor; Proteins; Proteome; Reporting; Resistance; Resistance development; Sesquiterpenes; Site; Southeastern Asia; Substrate Specificity; System; Testing; Therapeutic; Time; Tissues; Ubiquitin; Ursidae Family; Vertebral column; Zidovudine; analog; base; beta-Casein; design; global health; improved; in vitro Model; inhibitor/antagonist; multicatalytic endopeptidase complex; multidrug tolerance; oxidative damage; pharmacophore; prevent; prototype; residence; standard care; success; tuberculosis treatment

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.

项目摘要/摘要 尽管可以治愈，但疟疾是持续存在的全球健康危机，有超过2亿个使人衰弱的病例 年份和半百万的死亡，主要是五岁以下的儿童。恶性疟原虫（PF）已经发展 对所有抗疟药的抗性，包括主要的青蒿素（艺术）。艺术及其半合成 类似物被认为是疟疾治疗必不可少的。东南部的艺术阻力广泛 亚洲和非洲有越来越多的艺术抵抗报告。联合疗法是骨干 治疗结核病，癌症，艾滋病毒和疟疾。尽管组合取得了巨大成功 治疗，其有效性可以脱轨，因为两种药物的组合可能会成为事实上 在某些不可避免的情况下进行单一疗法。此外，PF对艺术影响的扩展暴露 多药公差。我们最近表明，针对PF蛋白酶体（PF20）的抑制剂可以杀死PF 其生命周期的每个阶段，并与艺术协同，克服艺术的抵抗力。在这个建议中，我们 假设我们称之为Artezomib（ATZ） - Art类似物和PF20的共价混合物 抑制剂 - 可以增强艺术作用并最大程度地减少对这两个组成部分的抗性的出现。我们 预测PF将活跃ATZ的艺术成分，就像ART本身一样，它将与PF蛋白结合； PF20将产生ATZ修饰的寡肽；和Pepperides与PF20的扩展接触 主动部位将增加ATZ的PF20抑制剂成分的结合，并克服 PF20S点突变可能导致的结合。与此一致，我们有 合成的ATZ比其成分PF20抑制剂更重要的PF20抑制剂，并且 这些ATZ具有抵抗野生型，PF20抑制剂耐药和耐药性K13 PF的潜力。我们现在 旨在探索AZTS的作用机理，并开发出更长的毒品样AZT 目标停留时间以杀死寄生虫，当他们退出生命周期的阶段 对艺术具有本质上的抵抗力。