Development of a Synergistic Drug Combination for Prevention and Treatment of Malaria

项目摘要 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，一次叮咬仅能将100个子孢子转移到蚊子体内。 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，寄生虫数量较少，以减少选择耐药突变体的可能性 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 是开发一种有效对抗恶性疟原虫的药物组合，恶性疟原虫是最致命的病原体， 致命的疟疾这种药物组合将协同作用，同时靶向肝脏、血液 以及对疾病传播至关重要的病媒阶段。我们和其他人的研究表明， ELQ-300针对所有3个生命周期阶段。我们拟议工作的最终目标是发展 一种廉价的ELQ-300前体药物，可以与其他抗疟药共同配制， 联合国儿童基金会和联合国艾滋病规划署将共同努力，预防和治疗疟疾，并支持全世界控制和消除这一疾病的努力。 本研究集中于ELQ-300前药与包括氯胍的双胍的组合。我们寻求一种 更好地了解抗疟协同作用的生化机制， ELQ-300和双胍。更好地理解这种相互作用将有助于设计双胍/ELQ-300 本发明提供了一种前药组合，其可安全用于人类每周预防和治疗疟疾。

Project Summary 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 drug combination that is active against P. falciparum, causative agent of the most virulent, often fatal form of malaria. The drug combination will act synergistically while targeting the parasite in the liver, blood and also the vector stages that are critical for disease transmission. Studies (by us and others) have shown that ELQ-300 targets all 3 of these life cycle stages. The ultimate objective of our proposed work is the development of an inexpensive ELQ-300 prodrug that can be co-formulated with other antimalarials in a synergistic combination to prevent and treat malaria and support the worldwide effort to control and eradicate the disease. This study focuses on the combination of ELQ-300 prodrugs with biguanides including proguanil. We seek a better understanding of the biochemical mechanism that underlies the antimalarial synergism that exists between ELQ-300 and biguanides. A better understanding of this interaction will help to design a biguanide/ELQ-300 prodrug combination that is safe for use in humans for weekly prophylaxis and treatment of malaria.