Establishment of a high throughput screen for the discovery of malaria transmissi

建立用于发现疟疾传播的高通量筛选

• 批准号: 7817440
• 负责人: Matthias Marti
• 金额: $ 50万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2010
• 资助国家: 美国
• 起止时间: 2010-09-29 至 2012-09-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/7817440
• 关键词: Animals; Antigens; Antimalarials; Appearance; Area; Award; Biological Assay; Biology; Blood; Blood Circulation; Cells; Chloroquine; Collaborations; Combined Modality Therapy; Country; Culicidae; Detection; Development; Disease; Dose; Drug usage; Erythrocytes; Falciparum Malaria; Follow-Up Studies; Foundations; Goals; Growth; Health; Human; In Vitro; Individual; Infection; Insecticides; Institutes; Laboratories; Lead; Libraries; Life; Link; Malaria; Mediating; Methods; Microscopic; Morbidity - disease rate; Parasite resistance; Parasites; Pattern; Performance; Persons; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Quinine; Reading; Research; Resistance; Series; Staging; Technology; Therapeutic; Transgenic Organisms; Treatment Failure; Vaccine Design; Vaccines; Work; asexual; base; disease transmission; drug development; drug discovery; feeding; high throughput screening; human morbidity; improved; killings; mefloquine-sulfadoxine-pyrimethamine; mortality; neglect; novel; novel strategies; prevent; programs; research study; small molecule; transmission process; vaccine development; vector mosquito

DESCRIPTION (provided by applicant): Establishment of a high throughput screen for the discovery of malaria transmission blocking drugs a major goal of the worldwide malaria eradication program is the reduction and eventual elimination of malaria transmission. In order to achieve this goal, the development of drugs to prevent transmission becomes a high priority and requires new approaches and assays. Herein we propose to develop a small molecule high throughput screen (HTS) focused on preventing the development of gametocytes, the form of malaria that mediates transmission. The goal of this work is the discovery of small molecules that could be developed into transmission blocking drugs. Efforts for the development of vaccines or antimalarial drugs have traditionally targeted the asexual stages of P.falciparum, while virtually neglecting transmission stages. Asexual stages are the proliferative stages during the parasite cycle in the human host, and can reach large numbers (up to 20% of all mature red blood cells in the body may be infected). Asexual development is also linked to the morbidity and mortality of falciparum malaria. However, the emergence of resistance against all currently used drugs (all of which target asexual stages) and unsuccessful attempts to develop vaccines based on asexual blood stage antigens highlight the importance of targeting transmission stages. The global campaign to eradicate malaria, initiated by the Bill and Melinda Gates foundation in 2007, has recognized that inhibiting transmission needs to be the top priority if we aim for eradication. There is a major focus on insecticide research, as well as on drugs and vaccines designed to block transmission of malaria from an infected person to additional hosts, by killing the sexual form of the parasite in the bloodstream or preventing maturation of the parasite within the mosquito. Unfortunately, little is known about the biology of transmission stages, and methods for in vitro culture and analysis are limited compared to asexual stage parasites. My laboratory has established a series of crucial technologies for the standardized culture, the detection and the quantification of these stages in vitro. In fact, these technologies enable us to propose the first high throughput assay with a library of 160,000 of chemically diverse compounds for the discovery of compounds that inhibit the development of malaria transmission stages. This project is a collaboration with the Broad Institute, which will be providing expertise in establishment and performance of the assay as well as compound libraries. This is a very important and timely project with great potential to contribute to improved health conditions in malaria endemic countries. Based on the hit rate of a recent whole cell P. falciparum assay (approximately 1%) at our proposed initial compound concentration, we anticipate identification of several hundred to a few thousand compounds that will be further investigated in dose-down screens. In addition, we will perform a microscopic analysis of corresponding parasite phenotypes to identify possible common patterns on growth inhibition or killing. Although beyond the scope of the experiments proposed for this award, lead compounds will be further analyzed in follow up studies such as secondary assays, animal studies, and through mechanism of action studies for target identification. This work will ultimately feed both a pipeline for further development of transmission blocking drugs and our continuous efforts to understand the biology of these elusive yet important parasite stages. A major goal of the worldwide malaria eradication program is the reduction and eventual elimination of malaria transmission. In order to achieve this goal, the development of drugs to prevent transmission becomes a high priority and requires new approaches and assays. Herein we propose to develop a small molecule high throughput screen (HTS) focused on preventing the development of gametocytes, the form of malaria that mediates transmission. The goal of this work is the discovery of small molecules that could be developed into transmission blocking drugs.

描述(申请人提供)：建立高通量筛查以发现疟疾传播阻断药物全球根除疟疾计划的主要目标是减少并最终消除疟疾传播。为了实现这一目标，开发预防传播的药物成为一项高度优先事项，需要新的方法和检测方法。在这里，我们建议开发一种小分子高通量筛选(HTS)，重点是防止配子细胞的发育，配子细胞是疟疾的媒介传播形式。这项工作的目标是发现可以开发成传播阻断药物的小分子。疫苗或抗疟疾药物的开发工作传统上是针对恶性疟原虫的无性阶段，而实际上忽视了传播阶段。无性生殖阶段是人体寄生虫周期中的增殖期，可达到大量(体内所有成熟红细胞中高达20%可能被感染)。无性发展也与恶性疟疾的发病率和死亡率有关。然而，对目前使用的所有药物(所有药物都针对无性阶段)出现抗药性，以及基于无性血期抗原开发疫苗的尝试失败，突显了以传播阶段为目标的重要性。比尔和梅林达·盖茨基金会于2007年发起的全球根除疟疾运动认识到，如果我们的目标是根除疟疾，就必须将遏制传播作为首要任务。主要的重点是杀虫剂研究，以及旨在通过杀死血液中寄生虫的有性形式或防止寄生虫在蚊子体内成熟来阻止疟疾从感染者传播到更多宿主的药物和疫苗。不幸的是，人们对传播阶段的生物学知之甚少，与无性阶段的寄生虫相比，体外培养和分析的方法也很有限。我的实验室已经建立了一系列关键技术，用于体外标准化培养、检测和量化这些阶段。事实上，这些技术使我们能够提出第一个高通量化验，该化验库包含16万种化学成分多样的化合物，用于发现抑制疟疾传播阶段发展的化合物。这个项目是与博德研究所的合作，博德研究所将提供建立和执行分析以及化合物文库的专业知识。这是一个非常重要和及时的项目，有很大潜力有助于改善疟疾流行国家的卫生条件。根据最近一次全细胞恶性疟原虫检测的命中率(约1%)，在我们建议的初始化合物浓度下，我们预计将鉴定数百至数千种化合物，这些化合物将在剂量下降筛选中进一步研究。此外，我们将对相应的寄生虫表型进行显微分析，以确定可能的生长抑制或杀死的共同模式。虽然超出了本奖项建议的实验范围，但先导化合物将在后续研究中进一步分析，如二次化验、动物研究，以及通过作用机制研究进行目标识别。这项工作最终将为进一步开发传播阻断药物提供管道，并为我们理解这些难以捉摸但重要的寄生虫阶段的生物学而继续努力。全球根除疟疾计划的一个主要目标是减少并最终消除疟疾传播。为了实现这一目标，开发预防传播的药物成为一项高度优先事项，需要新的方法和检测方法。在这里，我们建议开发一种小分子高通量筛选(HTS)，重点是防止配子细胞的发育，配子细胞是疟疾的媒介传播形式。这项工作的目标是发现可以开发成传播阻断药物的小分子。