Lipid mediated formation of hemozoin

描述（由申请人提供）：疟疾色素血红素（一种血红素的微晶二聚体）的形成是疟疾原虫疟原虫中被药物破坏的最重要过程之一，也是寄生蠕虫血吸虫的潜在药物靶点。然而，其形成和抑制机制目前尚不清楚。由于最近的证据表明，血色素蛋白的形成发生在脂滴（即脂肪）内，该项目旨在研究人工脂滴的特性和β -血素（合成血色素）在这些人工脂滴中的形成速率，以便更好地了解这一过程，并开发改进的方法来寻找新的β -血素抑制支架，作为发现抗疟疾和抗血吸虫药物的第一步。为实现这一目标，提出了以下具体目标：研究血红素与中性脂的相互作用。具体目标2。研究-血红素在脂/水界面和分散在水中的脂滴中的形成速率。具体目标3。将我们对脂滴介导的β -血红素形成的理解转化为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Timothy J. Egan和田纳西州纳什维尔范德比尔特大学的David W. Wright的合作项目进行。关于中性脂在水面上的行为、血红素与脂质的相互作用以及β -血红素形成速率的研究将在开普敦进行。高通量筛选的开发将在范德比尔特大学进行，然后将用于在范德比尔特大学的高通量筛选设施中筛选广泛的范德比尔特大学化合物库。这有望导致新的β -血红素抑制支架的鉴定。两家集团之间的合作将具有很强的协同效应。关于脂质介导的-血红素形成的大量专业知识，特别是关于这一过程速率的研究将从开普敦大学转移到范德比尔特大学。相反，高通量筛选方法的专业知识将从范德比尔特大学转移到开普敦大学。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，因此需要它们来解毒血红素。血红素是一种血红素的微晶二聚体，它的形成是疟疾寄生虫疟原虫中被药物破坏的最重要的过程之一，也是血吸虫的潜在靶点。然而，其形成和抑制机制目前尚不清楚。我们建议开展研究，以更好地了解这一过程，并利用这些知识开发筛选方法，以发现破坏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.