Optimizing ELQs for Treatment and Prevention of Malaria

与仅针对血液阶段的药物相比，针对肝脏阶段的药物提供了许多优势。第一, 抗肝病药物是真正的因果预防药物，可以预防所有疾病。 与疟疾有关的症状，包括死亡。其次，已经确定，虽然野生捕获的 蚊子可能携带数以千计的子孢子，只有H10子孢子会在一次叮咬中转移到 人类的主人。在接下来的2-3周内，子孢子在肝脏中繁殖，产生10,000-30,000 裂殖体破裂前的后代和寄生虫涌入血液，在那里绝对的寄生虫 负担可能增加到10万亿(1013)个循环疟原虫。显然，打击…… 寄生虫数量低的肝期，以减少选择耐药的可能性 并且在感染之前有机会削弱人类宿主的防御能力。我们的主要目标是 该项目旨在开发一种非喹啉类药物，对恶性疟原虫和间日疟原虫有效， 以肝脏和血液阶段的寄生虫为靶标，包括配子体。研究(由我们和其他人进行) 研究表明，内毒素样喹诺酮(ELQ)化学型针对所有3个生命周期阶段。这个 我们提议的工作的最终目标是开发一种可以共同制定的廉价的ELQ 与其他抗疟疾药物协同联合预防和治疗疟疾，并可用于协助 在世界范围内根除这种疾病。 我们对内毒素的研究表明，内毒素是由安德萨格在20世纪40年代发现的一种药物(S) 在哺乳动物身上表现不佳是因为它的代谢不稳定。最近，我们开发了ELQ 具有亚纳分子IC50值的类似物，对多药耐药和阿托瓦酮耐药寄生虫， 口服1 mg/kg/d对小鼠疟疾模型的疗效及对疟疾的预防作用 子孢子感染剂量为3 mg/kg/d(所研究的最低剂量)。在本申请中，我们寻求继续 探索喹诺酮类药物化学型周围的化学空间，以发展这一抗疟类药物 最大限度地发挥其潜力。正如在本提案的叙述中所描述的，我们已经发现了一个ELQ 对疟疾感染的小鼠有疗效的衍生物，0.1 mg/kg/天(4天)，通过多种途径 行政管理。本申请的具体目的是：1。引导ELQ抗疟疾药物的优化，2。 ELQ作用机制的表征(S)，以及3.ELQ抗性机制的表征 以及恶性疟原虫种群对ELQ抗性频率的评估。 人类使用的ELQ的开发可能会极大地改变疟疾的管理方式 全世界。因为ELQ对多个发育阶段的感染是有效的，所以它们可以用来 预防和治疗疟疾，也可以在根除这种疾病方面发挥重要作用。

Drugs targeting the liver stage offer many advantages over drugs that merely target the blood stage. First, drugs active against the liver stage represent true causally prophylactic agents that can prevent all disease symptoms, including death, associated with malaria. Secondly, it has been established that while wild-caught mosquitoes may harbor thousands of sporozoites, only H10 sporozoites are transferred in a single bite to the human host. Over the next 2-3 weeks the sporozoite reproduces in the liver to produce 10,000-30,000 descendants before the schizont ruptures and parasites flood into the bloodstream where the absolute parasite burden may increase to ten thousand billion (1013) circulating plasmodia. Clearly it is advantageous to strike at the liver stage where parasite numbers are low, to diminish the likelihood of selecting for a drug resistant mutant and before the infection has a chance to weaken the defenses of the human host. Our primary goal in this project is to develop a non-quinoline drug that is active against P. falciparum and P. vivax malaria, targeting the parasite in the liver and blood stages, and including the gametocytes. Studies (by us and others) have shown that the Endochin-like Quinolone (ELQ) chemotype targets all 3 of these life cycle stages. The ultimate objective of our proposed work is the development of an inexpensive ELQ that can be co-formulated with other antimalarials in a synergistic combination to prevent and treat malaria, and can serve to assist in eradication of the disease worldwide. Our study of endochin, a drug discovered by Andersag in the 1940's) showed that the primary cause of its poor performance in mammals is due to its metabolic instability. More recently we have developed ELQ analogs with subnanomolar IC50 values against multidrug resistant and atovaquone resistant parasites, curative efficacy in murine models of malaria at oral doses of 1mg/kg/day, as well as prophylaxis against sporozoite induced infections at 3mg/kg/day (the lowest dose studied). In this application we seek to continue to explore the chemical space around the quinolone chemotype in order to develop this antimalarial class to the fullest of its potential. As described in the narrative of this proposal we have already discovered an ELQ derivative that is curative in malaria infected mice at 0.1mg/kg/day (4 days) via multiple routes of administration. The Specific Aims of this application are: 1. Lead optimization of ELQ antimalarials, 2. Characterization of the ELQ mechanism(s) of action, and 3. Characterization of ELQ resistance mechanisms and assessment of ELQ resistance frequency in populations of P. falciparum parasites. Development of an ELQ for human use could dramatically change the way in which malaria is managed worldwide. Because ELQs are active against multiple developmental stages of infection they could be used to prevent and treat malaria and also could have a major role in eradicating the disease.