Optimizing ELQs for Treatment and Prevention of Malaria

描述(由申请人提供)：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。首先，对肝脏阶段有效的药物是真正的因果预防药物，可以预防与疟疾有关的所有疾病症状，包括死亡。其次，已经确定，虽然野生捕获的蚊子可能携带数千个子孢子，但只有H10子孢子在一次叮咬中转移到人类宿主。在接下来的2-3周内，子孢子在肝脏中繁殖，在裂殖体破裂和寄生虫涌入血液之前产生10,000-30,000个后代，在那里寄生虫的绝对负担可能增加到10万亿(1013)个循环疟原虫。显然，在寄生虫数量较低的肝脏阶段进行攻击，减少选择耐药突变株的可能性，并在感染有机会削弱人类宿主的防御之前，是有利的。我们在这个项目中的主要目标是开发一种非喹啉类药物，对恶性疟原虫和间日疟原虫有效，针对肝脏和血液阶段的寄生虫，包括配子细胞。我们和其他人的研究表明，内毒素样喹诺酮(ELQ)化学类型针对所有这三个生命周期阶段。我们拟议工作的最终目标是开发一种廉价的ELQ，它可以与其他抗疟疾药物以协同组合的方式共同配制，以预防和治疗疟疾，并可帮助在世界各地根除这种疾病。我们对内毒素的研究表明，其在哺乳动物中表现不佳的主要原因是其代谢不稳定。最近，我们开发了具有亚纳米分子IC50值的ELQ类似物，以对抗多药耐药和阿托瓦酮耐药的寄生虫，在小鼠疟疾模型中口服剂量为1 mg/kg/天的疗效，以及预防子孢子诱导的感染以3 mg/kg/天(研究的最低剂量)。在这项申请中，我们寻求继续探索喹诺酮类化疗药物周围的化学空间，以便最大限度地发挥这一抗疟疾药物的潜力。正如这项提案的叙述中所描述的那样，e已经发现了一种ELQ衍生物，它通过多种给药途径，以0.1 mg/kg/天(4天)的速度治愈疟疾感染的小鼠。这一应用的具体目的是：1.引导ELQ抗疟药的优化；2.ELQ作用机制(S)的表征；3.ELQ抗性机制的表征和恶性疟原虫种群中ELQ抗性频率的评估。开发供人类使用的ELQ可能会极大地改变全球疟疾管理的方式。由于ELQ对感染的多个发展阶段有积极作用，它们可以用于预防和治疗疟疾，也可以在根除这种疾病方面发挥重要作用。

DESCRIPTION (provided by applicant): 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 e 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.