Optimizing ELQs for Treatment and Prevention of Malaria

描述（由申请人提供）：针对肝脏阶段的药物比仅针对血液阶段的药物具有许多优势。首先，对肝脏阶段有活性的药物是真正的因果预防剂，可以预防与疟疾有关的所有疾病症状，包括死亡。其次，已经确定的是，虽然野生捕获的蚊子可能携带数千个孢子虫，但在一次叮咬中只有约10个孢子虫被转移到人类宿主。在接下来的2-3周内，孢子子在肝脏中繁殖，产生10,000-30,000个后代，然后分裂体破裂，寄生虫涌入血液，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，在寄生虫数量较少的肝脏阶段进行打击是有利的，以减少选择耐药突变体的可能性，并且在感染有机会削弱人类宿主的防御之前。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活性，针对肝脏和血液阶段的寄生虫，包括配子体。我们和其他人的研究表明，内啡肽样喹诺酮（ELQ）化学型靶向所有这3个生命周期阶段。我们提出的工作的最终目标是开发一种廉价的低剂量抗疟药，可以与其他抗疟药协同配制，以预防和治疗疟疾，并有助于在全世界消灭这种疾病。我们对内chin（一种由Andersag在20世纪40年代发现的药物）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摩尔IC50值的ELQ类似物，可治疗多药耐药和阿托伐酮耐药寄生虫，口服剂量为1mg/kg/天对疟疾小鼠模型有疗效，以及口服剂量为3mg/kg/天（所研究的最低剂量）可预防孢子虫引起的感染。在这个应用程序中，我们寻求继续探索围绕喹诺酮类化学型的化学空间，以开发这类抗疟疾药物，以充分发挥其潜力。如本提案的叙述所述，我们已经发现了一种ELQ衍生物，通过多种给药途径，每天0.1mg/kg（4天）对感染疟疾的小鼠有效。本应用程序的具体目的是：1。2. ELQ抗疟药的先导物优化；2 . ELQ作用机制的表征；恶性疟原虫ELQ耐药机制特征及ELQ耐药频率评估。开发一种供人类使用的ELQ可能会极大地改变全世界管理疟疾的方式。由于elq对感染的多个发育阶段都有活性，它们可以用来预防和治疗疟疾，也可以在根除疟疾方面发挥重要作用。

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 ~10 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.