Development of Drugs that Target the Malaria Hexose Transporter

 描述(申请人提供)：疟疾化疗对引入该领域的药物产生了抗药性。目前推出的青蒿素联合疗法(ACTs)是为了限制耐药性，但对青蒿素反应缓慢的菌株现在已经在东南亚出现，有可能取代目前对抗这一广泛传播的祸害的最佳疗法。因此，人们迫切要求开发针对不同靶点而不是ACTs的新型抗疟疾药物。药物开发的一个有希望的目标是通过恶性疟原虫六糖转运体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可用，并通过糖酵解低效地代谢大量葡萄糖。因此，这些寄生虫的生存严重依赖于通过PFHT摄取葡萄糖。基因和化学方法都证实了PFHT是一种药物靶点。因此，pfht基因不能被敲除，而选择性抑制pfht转运功能的葡萄糖类似物，与高度序列差异的人类葡萄糖转运体相比，在体外和疟疾小鼠模型中都对寄生虫是致命的。然而，目前的挑战是寻找能够选择性抑制PFHT的类药物化合物，以作为新药开发的先导。在前期工作中，我们筛选了几个具有体外抗疟疾活性的重点化合物文库，并发现了几个选择性抑制PFHT对人GLUT1的命中。这项提议将进一步推动这些化合物及其类似物朝着靶向PFHT的口服生物利用药的发展。此外，还将对可能抑制疟疾生长的不同疟疾活性物库进行筛选，以寻找其他选择性的PFHT抑制剂。这些疟疾活性物质代表了一个小的集中化合物库，这些化合物具有理想的疟疾生长抑制特性，是从125万种化合物的表型筛选中提取出来的，因此大大扩大了最初询问的化学空间。这些多重筛选具有提供各种化学支架的潜力，这些支架可以有效地抑制PFHT和寄生虫的生长，并可以作为药物开发的新线索。这一探索性的R21提案的主要目标是确定多种化学支架，这些支架可以通过抑制葡萄糖的摄取来开发新的抗疟疾药物，葡萄糖是疟疾寄生虫的关键营养物质。

 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.