Development of Drugs that Target the Malaria Hexose Transporter

开发针对疟疾己糖转运蛋白的药物

• 批准号: 8968767
• 负责人: Scott M Landfear
• 金额: $ 23.1万
• 依托单位: OREGON HEALTH & SCIENCE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2017-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8968767
• 关键词: Affinity; Antimalarials; Artemisinins; Bioavailable; Blood; Blood Circulation; Boxing; Cell physiology; Cessation of life; Chemicals; Cholesterol; Collection; Combined Modality Therapy; Communicable Diseases; Culicidae; Development; Disease; Drug Targeting; Drug resistance; Erythrocytes; Essential Genes; FDA approved; Family; Genes; Glucose; Glucose Transporter; Glycolysis; Growth; Hexose Transporter; Human; In Vitro; Infection; Insecta; Intestines; Knock-out; Laboratories; Lead; Leishmania; Libraries; Life; Life Cycle Stages; Liver; Malaria; Membrane Transport Proteins; Methods; Molecular Target; Nutrient; Oral; Parasites; Pathology; Pharmaceutical Preparations; Plasmodium falciparum; Property; Reporting; Resistance; Resistance development; SLC2A1 gene; Schering-Plough brand of ezetimibe; Scourge; Selective Serotonin Reuptake Inhibitor; Southeastern Asia; Staging; System; Work; analog; artemisinine; chemical genetics; chemotherapy; drug development; drug discovery; genetic approach; global health; glucose analog; glucose uptake; in vitro activity; inhibitor/antagonist; killings; knockout gene; mouse model; novel; permease; public health relevance; resistant strain; scaffold; screening; sodium-translocating ATPase; stem; transmission process; uptake

 DESCRIPTION (provided by applicant): Malaria chemotherapy has suffered from development of resistance against drugs introduced to the field. Current Artemisinin Combination Therapies (ACTs) were introduced to limit drug resistance, but strains that respond slowly to artemisinin have now arisen in Southeast Asia, threatening to displace the best current therapy against this widespread scourge. As a result, there have been urgent calls for development of novel antimalarial drugs that act against different targets than ACTs. One promising target for drug development is the uptake of glucose via the Plasmodium falciparum hexose transporter, PfHT. Malaria parasites live inside red blood cells in the stages that cause disease, have abundant glucose available in the blood, and metabolize large amounts of glucose inefficiently by glycolysis. Hence, these parasites are critically dependent on uptake of glucose through PfHT for survival. PfHT has been validated as a drug target by both genetic and chemical methods. Thus the PfHT gene cannot be knocked out, and glucose analogs that selectively inhibit the transport function of PfHT, versus the highly sequence- divergent human glucose transporters, are lethal to the parasite both in vitro and in a mouse model of malaria. However, the current challenge is to identify drug-like compounds that selectively inhibit PfHT that can serve as leads for development of new drugs. In preliminary work, we have screened several focused libraries of compounds with demonstrated antimalarial activity in vitro and discovered several hits that selectively inhibit PfHT versus human GLUT1. This proposal will further advance these compounds, and analogs thereof, toward development of orally bioavailable drugs that target PfHT. In addition, a different library of Malaria Actives that potenly inhibit malaria growth will be screened for other selective inhibitors of PfHT. These Malaria Actives represent a small focused library of compounds with ideal properties as inhibitors of malaria growth and were distilled from a phenotypic screen of 1.25 million compounds, thus widening considerably the initial chemical space interrogated. These multiple screens have the potential to deliver diverse chemical scaffolds that potently inhibit PfHT and parasite growth and can serve as novel leads for drug development. The major objective of this exploratory R21 proposal is to identify multiple chemical scaffolds that can be exploited subsequently for development of new antimalarial drugs via their ability to inhibit uptake of glucose, a critical nutrient for the malaria parasite.

 描述（由申请人提供）：疟疾化疗已经遭受了对引入该领域的药物的耐药性的发展。目前的青蒿素联合疗法（ACTs）是为了限制耐药性而引入的，但对青蒿素反应缓慢的菌株现已在东南亚出现，有可能取代目前针对这一广泛祸害的最佳疗法。因此，迫切需要开发针对与青蒿素综合疗法不同靶点的新型抗疟药物。药物开发的一个有前景的目标是通过恶性疟原虫己糖转运蛋白PfHT摄取葡萄糖。疟疾寄生虫在致病阶段生活在红细胞内，血液中有丰富的葡萄糖，并通过糖酵解代谢大量葡萄糖。因此，这些寄生虫的生存严重依赖于通过PfHT摄取葡萄糖。PfHT已通过遗传和化学方法被验证为药物靶标。因此，PfHT基因不能被敲除，相对于高度序列差异的人葡萄糖转运蛋白，选择性抑制PfHT转运功能的葡萄糖类似物在体外和小鼠疟疾模型中对寄生虫都是致命的.然而，目前的挑战是鉴定选择性抑制PfHT的药物样化合物，其可以作为新药开发的先导。在初步工作中，我们已经筛选了几个集中的化合物库，这些化合物具有体外抗疟活性，并发现了几个选择性抑制PfHT与人GLUT 1的命中。该提议将进一步推进这些化合物及其类似物，以开发靶向PfHT的口服生物可利用药物。此外，将筛选有效抑制疟疾生长的疟疾活性物质的不同文库中的PfHT的其他选择性抑制剂。这些疟疾活性物质代表了一个小型的化合物集中库，这些化合物具有作为疟疾生长抑制剂的理想特性，并且是从125万种化合物的表型筛选中提取出来的，从而大大拓宽了最初的化学空间。这些多重筛选有可能提供多种化学支架，有效抑制PfHT和寄生虫生长，并可作为药物开发的新先导。这项探索性的R21提案的主要目标是确定多种化学支架，这些支架随后可以通过抑制葡萄糖摄取的能力来开发新的抗疟药物，葡萄糖是疟疾寄生虫的关键营养素。