Target-Based High-Throughput Screens for Plasmodium falciparum Malaria

描述(申请人提供)：迫切需要用于治疗疟疾的新的治疗剂，疟疾是世界上最致命的寄生虫病。疟疾困扰着3亿至5亿人，每年导致100至200万人死亡，在撒哈拉以南非洲，与疟疾有关的所有死亡人数中有85%以上是幼儿和孕妇。耐多药寄生虫的出现，特别是在恶性疟原虫(尤其是氯喹)中的出现，导致疟疾在发展中世界的大部分地区死灰复燃和传播。理想的新抗疟疾药物应该是：针对寄生虫，针对寄生虫生长所必需的过程，并对耐多药寄生虫株具有高度活性。从历史上看，氯喹是最重要和最有效的抗疟疾药物，因为它极低的成本，高效率，是寄生虫特有的过程。鉴于这些特性，氯喹仍然是值得效仿的药物。现在有相当多的证据表明，氯喹和相关的4-氨基喹啉化合物通过干扰疟疾寄生虫中血吸虫的形成而发挥作用。因此，目前需要的是针对寄生虫中血球蛋白形成的新的化疗药物。寻找这种新的化疗药物最有效的方法是开发新的基于靶点的分析方法，这种方法将用于高通量筛选结构多样化的小分子文库。这项提案概述了血红素结晶分析的发展，该分析技术简单、健壮，并与HTS从结构多样化的小分子库中识别抑制性小分子所需的自动化相兼容。迫切需要治疗疟疾这一世界上最致命的寄生虫病的新的治疗剂。在这里，我们将开发一种新的基于靶点的分析方法来筛选结构多样化的小分子文库，以确定新的抗疟疾药物来杀死寄生虫。

DESCRIPTION (provided by applicant): New therapeutic agents for the treatment of malaria, the world's most deadly parasitic disease, are urgently needed. Malaria afflicts 300-500 million people and results in 1-2 million deaths annually and more than 85% of all malaria related mortality is to young children and pregnant women in Sub-Saharan Africa. The emergence of multi-drug resistant parasites, particularly in Plasmodium falciparum (especially to chloroquine) has led to the resurgence and spread of malaria in large parts of the developing world. An ideal new antimalarial agent should: be specific for the parasite, target a process that is essential for parasite growth, and be highly active against multi-drug resistant parasite strains. Historically, chloroquine was the most important and effective antimalarial drug due to its extremely low cost, high efficacy and is a process unique to the parasite. In light of these properties chloroquine is still the drug to emulate. There is now considerable evidence to suggest that chloroquine and related 4-aminoquinoline compounds act by interfering with hemozoin formation in the malaria parasite. Thus, what is currently needed is new chemotherapeutics that target hemozoin formation in the parasite. The most effective method to find such new chemotherapeutic agents is to develop new target-based assays that will be used to perform high-throughput screening of structurally diverse small molecule libraries. This proposal outlines the development of a heme crystallization assay that is technically simple, robust, and compatible with the automation necessary for HTS to identify inhibitory small molecules from structurally diverse small molecule libraries. New therapeutic agents for the treatment of malaria, the world's most deadly parasitic disease, are urgently needed. Here we will develop a new target-based assay to screen structurally diverse small molecule libraries to identify new antimalarial agents to kill the parasite.