Hematin crystallization in Plasmodium parasites

总结 疟原虫实现血红素解毒的主要机制是 螯合血红素作为无毒的结晶疟原虫色素。血红素螯合一直是 最成功的抗疟疾药物分子靶点。尽管经过多年努力， 关于血红素解毒机制的基本问题仍然难以捉摸。不 明确药物是否通过与血红素形成可溶性复合物来抑制结晶，或 与疟原虫色素表面相互作用。其他悬而未决的问题涉及到详细的分子 抑制机制和疟原虫色素表面上的特定位点的存在， 不同的抗疟药是否利用相似或不同的机制， 以及青蒿素衍生物是否干扰血红素解毒。我们建议，首先 时间在抗疟研究，以阐明抑制晶体的分子机制 并提供疟原虫色素上相关活性位点的原子级细节 晶体表面我们将追求两个具体目标：1。建立行动机制， 阻断几类抗疟药物和相关化合物的血红素结晶。 2.提供血红素掺入晶体的活性位点的原子水平视图， 与抗疟药物的关联，并监测与抗疟药物关联的动态 这些网站在真实的时间。我们的主要研究方法是时间分辨的原位原子力 原子力显微镜（AFM），包括原子分辨率AFM，开创了血红素的研究 是我们集团的结晶。完成这里提出的工作将指导我们进行更多的工作。 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 根据药物在结晶抑制方面的效力对药物进行排名，并探索 晶体响应于由于血红素积累而增加的过饱和度。 实现目标2将为最先进的分子动力学建模（使用 量子力学势和明确的溶剂），以解决药物-血红素相互作用， 解决方案和阐明药物结合模式的晶体表面。这种模式将演变成一种 合理设计新型抗疟药物平台，将与医药部门合作开发 化学家和寄生虫学家研究寄生虫抑制，药物生物利用度和功效。

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.