Novel Therapeutics to Target Parasite Cytochrome bc1

项目总结/摘要 疟疾药物风险投资公司（MMV）最近发布了一份“路线图”， 这是支持消灭和根除疟疾长期目标所必需的。路线图包括一个愿望清单 目标候选概况（TCP）和药物（目标产品概况，即，TPP）。最新修订的 针对抗疟疾候选靶点和产品概况，MMV强调需要确定新的快速 在需要其他药物进行化学保护和化学治疗的同时， 用长效分子，和/或肠胃外制剂（即，TCP-2）（Burrows，JN等人，2017, Malaria Journal，16：26）。根据他们更新的路线图，需要新药来保护人口 在消灭疟疾的最后阶段进入高流行地区。以及会引起肝脏病变的药物- 化学预防需要阶段活性以防止疟疾期间感染或抗性爆发 季这种TCP是以复方药物阿托伐醌+氯胍为模型的。 作为寄生虫细胞色素bc 1复合物的有效和选择性抑制剂，ELQ-300选择性靶向 恶性疟原虫在血液和肝脏阶段，甚至杀死寄生虫在中肠发展， 蚊媒。与阿托伐醌不同，ELQ-300是靶酶复合物的Qi位点的选择性抑制剂。 在美国国立卫生研究院和美国国防部的支持下，我们成功地开发了一种口服前药制剂， ELQ-331用于人类每周预防疟疾。在本申请中，我们寻求NIH 支持开发更有效和全面抑制寄生虫的ELQ衍生物的工作 细胞色素bc 1复合物初步数据支持改进ELQ结构的先进设计 提供的应用程序以及我们广泛的知识，内缩素样喹诺酮衍生物， 恶性疟原虫细胞色素bc 1 Qo或Qi位点的抑制剂。上级分子将通过 用于评估选择效力和缺乏哺乳动物细胞毒性的向下选择试验级联， 代谢稳定性、在模拟肠液中的溶解度、抗性倾向和作用方式以及 对小鼠血液和肝脏阶段疟疾的有效性。将探索上级分子的前药，以评估 用于增强口服生物利用度和抗疟性能。

Project Summary / Abstract The Medicines for Malaria Venture (MMV) recently published a “roadmap” for the types of medicines that are needed to support the long-term goal of malaria elimination and eradication. The roadmap consists of a wish list of target candidate profiles (TCP) and medicines (target product profiles, i.e., TPP). With the most recent revision to the anti-malarial target candidates and product profiles the MMV highlighted the need for identifying new rapid acting medicines for active case management while other drugs are needed for chemo-protection and chemo- prevention with long-acting molecules, and/or parenteral formulations (i.e., TCP-2) (Burrows, JN et al., 2017, Malaria Journal, 16:26). According to their updated roadmap new drugs are needed to protect populations entering areas of high endemicity during the final stages of malaria elimination. And drugs with causal liver- stage activity are needed for chemoprevention to prevent infection or outbreak of resistance during malarial seasons. This TCP has been modeled on the combination drug atovaquone + proguanil. As a potent and selective inhibitor of the parasite’s cytochrome bc1 complex ELQ-300 selectively targets Plasmodium falciparum in the blood and liver stages and even kills parasites developing in the midgut of the mosquito vector. Unlike atovaquone, ELQ-300 is a selective inhibitor of the Qi site of the target enzyme complex. With support from the NIH and US DOD we have been successful in developing an oral formulation of prodrug ELQ-331 for use in humans for weekly prophylaxis against malaria. In the present application we seek NIH support for work to develop ELQ derivatives that more effectively and comprehensively inhibit the parasite cytochrome bc1 complex. Advanced designs for improved ELQ constructs are supported by preliminary data provided with the application as well as our extensive knowledge of Endochin-Like Quinolone derivatives as inhibitors of the Plasmodium falciparum cytochrome bc1 Qo or Qi sites. Superior molecules will advance through a down-selection test cascade for assessment of selective potency and lack of mammalian cytotoxicity, metabolic stability, solubility in simulated intestinal fluids, resistance propensity and mode of action as well as efficacy against blood and liver stage malaria in mice. Prodrugs of superior molecules will be explored to assess for enhancement of oral bioavailability and antimalarial performance over parent molecules.