Hematin crystallization in Plasmodium parasites

疟原虫寄生虫中的血红素结晶

• 批准号: 9169162
• 负责人: PETER G VEKILOV
• 金额: $ 20.28万
• 依托单位: UNIVERSITY OF HOUSTON
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-06-16 至 2018-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9169162
• 关键词: Active Sites; Address; Antimalarials; Artemisinins; Atomic Force Microscopy; Binding; Biological Availability; Cell Nucleus; Chloroquine; Collaborations; Complex; Crystallization; Crystallography; Data; Disease; Drug Binding Site; Drug Metabolic Detoxication; Drug Targeting; Event; Growth; Hematin; Heme; Hemoglobin; Image; In Situ; Investigation; Isomerism; Malaria; Mechanics; Methods; Modeling; Molecular; Molecular Target; Monitor; Parasites; Pathway interactions; Pharmaceutical Preparations; Phase; Physiology; Plasmodium; Powder dose form; Research; Resolution; Route; Site; Solvents; Staging; Stereoisomer; Structure; Surface; Testing; Time; Transport Vesicles; Vacuole; Work; X-Ray Tomography; analog; artemisinine; base; design; dimer; hemozoin; inhibitor/antagonist; insight; molecular dynamics; molecular recognition; quantum; quinoline; quinoline analog; solute

Summary The main mechanism of heme detoxification implemented by Plasmodium parasites is the sequestration of heme as non-toxic, crystalline hemozoin. Heme sequestration has been the most successful molecular target for antimalarial drugs. Despite many years of effort, fundamental questions regarding the mechanism of heme detoxification remain elusive. It is not clear whether the drugs inhibit crystallization by forming soluble complexes with hematin, or interact with the hemozoin surface. Other open questions relate to the detailed molecular mechanism of inhibition and the existence of specific sites on the hemozoin surface that are active in drug binding, to whether different antimalarials utilize similar or different mechanisms and whether artemisinin derivatives interfere with heme detoxification. We propose, for the first time in antimalarial research, to elucidate the molecular mechanisms of inhibition of crystal growth by antimalarials and provide atomic-level detail of the relevant active sites on hemozoin crystal surfaces. We will pursue two specific aims: 1. Establish the mechanisms of action in blocking hematin crystallization of several classes of antimalarial drugs and related compounds. 2. Provide an atomic-level view of the active sites for hematin incorporation into crystals and association of the antimalarials and monitor the dynamics of antimalarial drug association with these sites in real time. Our main method of investigation is time-resolved in situ atomic force microscopy (AFM), including atomic resolution AFM, pioneered for studies of hematin crystallization by our group. Completion of the work proposed here will guide us to additional fundamental issues of heme detoxification and its inhibition. Achieving aim 1 will allow us to rank the drugs according to their potency in crystallization inhibition and explore how the crystals respond to the increased supersaturation due to the accumulation of hematin. Achieving aim 2 will provide the basis for state-of-the-art molecular dynamics modeling (using quantum mechanical potentials and explicit solvent) to address drug-hematin interactions in solution and elucidate drug binding modes on crystal surfaces. Such modeling will evolve into a platform for rational design of new antimalarials, to be developed in collaboration with medicinal chemists and parasitologists to study parasite suppression, drug bioavailability, and efficacy.

摘要 疟原虫实现血红素解毒的主要机制是 将血红素作为无毒、结晶的血球蛋白进行隔离。血红素封存一直是 最成功的抗疟疾药物的分子靶点。尽管多年来的努力， 关于血红素解毒机制的基本问题仍然难以捉摸。它不是 明确药物是否通过与血红素形成可溶的络合物来抑制结晶，或者 与血球蛋白表面相互作用。其他悬而未决的问题与详细的分子相关 抑制机制及其在血球蛋白表面存在的特定部位 药物结合的活性，取决于不同的抗疟疾药物是否使用相似或不同的机制 以及青蒿素衍生物是否会干扰血红素的解毒作用。我们建议，第一次 在抗疟疾研究中，阐明抑制晶体的分子机制 抗疟疾药物的生长，并提供血球蛋白上相关活性部位的原子水平详细信息 水晶面。我们将追求两个具体目标：一、建立 阻断几类抗疟疾药物及相关化合物的血红素结晶。 2.提供血红素结合到晶体中的活性位置的原子水平视图 抗疟疾药物的联合和监测抗疟疾药物联合的动态 这些网站都是实时的。我们的主要研究方法是时间分辨原位原子力 显微镜(AFM)，包括原子分辨率AFM，是研究血红素的先驱 我们团队的结晶。完成这里提出的工作将指导我们进行其他工作 血红素解毒及其抑制的基本问题。实现目标1将使我们能够 根据药物抑制结晶的效力对药物进行排序，并探索如何 由于血红素的积累，晶体对增加的过饱和度做出反应。 实现目标2将为最先进的分子动力学建模(使用 量子力学势和显式溶剂)来处理药物与血红素之间的相互作用 解决并阐明药物在晶体表面的结合模式。这样的建模将演变成一个 合理设计新抗疟疾药物的平台，将与Medical合作开发 化学家和寄生虫学家研究寄生虫抑制、药物生物利用度和疗效。