Lipid mediated formation of hemozoin

描述(申请人提供)：疟疾色素血球蛋白的形成，是一种血红素的微晶二聚体，是原生动物疟疾寄生虫疟原虫中最重要的药物干扰过程之一，也是寄生蠕虫血吸虫的潜在药物靶标。然而，目前对其形成和抑制的机制知之甚少。由于最近的证据表明，血虫蛋白的形成发生在脂质(即脂肪)液滴中，该项目旨在研究人造脂滴的特征和在这些人造脂滴中形成β-血红素(合成血球蛋白)的速率，以便更好地了解这一过程，并开发改进的方法，寻找新的β-血红素抑制支架，作为发现抗疟疾和抗血吸虫药物的第一步。为了实现这一目标，提出了以下具体目标：特定目的1.研究血红素与中性脂质的相互作用。特异目的2.研究β-血红素在脂质/水界面和分散在水中的脂滴中的形成速率。具体目的3.将我们对脂滴介导的β-血红素形成的理解转化为对潜在新药支架的高通量筛选。为了实现这些目标，这项研究将作为南非开普敦大学的蒂莫西·J·伊根和田纳西州纳什维尔范德比尔特大学的大卫·W·赖特的合作项目进行。将在开普敦进行关于中性脂质在水面的行为、血红素与脂质的相互作用以及β-血红素形成速率的研究。高通量筛网的开发将在范德比尔特大学进行，然后将用于在该大学的高通量筛查设施中对范德比尔特大学广泛的大院图书馆进行筛查。这有望导致新的贝塔-血红素抑制支架的识别。这两个小组之间的合作将具有很强的协同性。在脂质介导的β-血红素形成方面的大量专业知识，特别是关于这一过程的速率的研究，将从开普敦大学转移到范德比尔特大学。相反，高通量筛查方法的专业知识将从范德比尔特大学转移到开普敦大学。与公共卫生相关疟疾和血吸虫病是影响全世界数亿人的两种最重要的人类寄生虫病。这两种寄生虫都以血液为食，因此需要它们为血红素解毒。血球蛋白是一种血红素的微晶二聚体，是疟疾寄生虫中最重要的药物干扰过程之一，也是蠕虫寄生虫血吸虫的潜在靶标。然而，目前对其形成和抑制的机制知之甚少。我们建议进行研究，以更好地了解这一过程，并利用这一知识开发筛选方法，以发现扰乱这一过程的新化合物，作为发现新的抗疟疾和抗血吸虫药物的第一步。

DESCRIPTION (provided by applicant): Formation of the malarial pigment hemozoin, a microcrystalline dimer of heme, is one of the most important processes disrupted by drugs in the protozoan malaria parasite Plasmodium and is also a potential drug target in the parasitic helminth worm Schistosoma. However, the mechanism of its formation and inhibition is currently poorly understood. Since recent evidence suggests that hemozoin formation occurs within lipid (i.e. fat) droplets, the project aims to investigate the characteristics of artificial lipid droplets and the rates of beta-hematin (synthetic hemozoin) formation in these artificial lipid droplets in order to better understand the process and to develop improved methods for finding new beta-hematin inhibiting scaffolds as a first step to the discovery of antimalarial and antischistosomal drugs. To achieve this, the following specific aims are proposed: SPECIFIC AIM 1. Investigate the interaction of heme with neutral lipids. SPECIFIC AIM 2. Study the rate of beta-hematin formation at lipid/water interfaces and in lipid droplets dispersed in water. SPECIFIC AIM 3. Translate our understanding of lipid droplet mediated beta-hematin formation into a high throughput screen for potential new drug scaffolds. In order to achieve these goals, the research will be conducted as a collaborative project between Timothy J. Egan at the University of Cape Town, South Africa and David W. Wright at Vanderbilt University, Nashville, TN. Studies on the behavior of neutral lipids at water surfaces and of the interaction of heme with lipids as well as on the rates of beta-hematin formation will be conducted in Cape Town. Development of the high throughput screen will be conducted at Vanderbilt University and will then be used to screen the extensive Vanderbilt University compound library at the University's high throughput screening facility. This is expected to lead to the identification of new beta-hematin inhibiting scaffolds. The collaboration between the two groups will be strongly synergistic. The considerable expertise on lipid mediated beta-hematin formation and especially studies on the rates of this process will be transferred from the University of Cape Town to Vanderbilt University. Conversely, expertise on high throughput screening methods will be transferred from Vanderbilt University to the University of Cape Town. PUBLIC HEALTH RELEVANCE Malaria and schistosomiasis are the two most important human parasitic diseases affecting hundreds of millions of people around the world. Both parasites feed on blood with the consequent need for them to detoxify heme. Formation of hemozoin, a microcrystalline dimer of heme, is one of the most important processes disrupted by drugs in the malaria parasite Plasmodium and is also a potential target in the helminth parasite Schistosoma. However, the mechanism of its formation and inhibition is currently poorly understood. We propose to undertake research to better understand the process and to use this to knowledge to develop screening methods for discovering new compounds that disrupt the process as a first step to discovery of new antimalarial and antischistosomal drugs.