Optimizing ELQs for Treatment and Prevention of Malaria

靶向肝脏阶段的药物比仅靶向血液阶段的药物具有许多优势。第一、 对肝脏阶段有活性的药物是真正的病因预防剂，可以预防所有疾病 与疟疾有关的症状，包括死亡。第二，已经确定，虽然野生捕获 蚊子可能携带数千个子孢子，只有H10子孢子在一次叮咬中转移到蚊子体内。 人类宿主在接下来的2-3周内，子孢子在肝脏中繁殖，产生10，000 - 30，000个 在寄生虫破裂和寄生虫涌入血液之前， 负担可能会增加到一万亿（1013）循环疟原虫。显然，打击 肝脏阶段，寄生虫数量较低，以减少选择抗药性的可能性 突变体和感染之前有机会削弱人类宿主的防御。我们的主要目标是 该项目是开发一种对恶性疟原虫和间日疟原虫疟疾有效的非喹啉药物， 针对肝脏和血液阶段的寄生虫，包括配子母细胞。研究（我们和其他人） 已经表明内毒素样喹诺酮（ELQ）化学型靶向所有3个生命周期阶段。的 我们所提出的工作的最终目标是开发一种廉价的、可以共同制定的ELQ 与其他抗疟药协同组合，以预防和治疗疟疾， 在全世界范围内消灭这种疾病。 我们对安德萨格在20世纪40年代发现的一种药物-恩多钦的研究表明， 在哺乳动物中表现不佳是由于其代谢不稳定。最近，我们开发了ELQ 对多药耐药和阿托伐醌耐药寄生虫具有亚纳摩尔IC 50值的类似物， 口服剂量为1 mg/kg/天的疟疾小鼠模型的疗效，以及预防 子孢子在3 mg/kg/天（研究的最低剂量）下诱导感染。在本申请中，我们寻求继续 探索喹诺酮化学类型周围的化学空间，以开发这种抗疟疾药物， 充分发挥其潜力。正如本提案的叙述中所述，我们已经发现了一个ELQ 在疟疾感染的小鼠中以0.1mg/kg/天（4天）通过多种途径治疗的衍生物 局本申请的具体目的是：1.领导优化ELQ抗疟药，2。 ELQ作用机制的表征，以及3. ELQ抗性机制的表征 和评估恶性疟原虫群体中ELQ抗性频率。 开发人类使用的ELQ可能会极大地改变疟疾的管理方式 国际吧由于ELQ对感染的多个发育阶段具有活性，因此它们可用于 预防和治疗疟疾，也可以在消灭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.