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

项目摘要 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≈10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，以减少选择耐药突变株的可能性 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 是开发一种对恶性疟原虫有效的药物组合，恶性疟原虫是最致命的病原体，通常 致命的疟疾形式。当针对肝脏、血液中的寄生虫时，药物组合将发挥协同作用 以及对疾病传播至关重要的媒介阶段。(我们和其他人)的研究表明 ELQ-300针对的是所有这3个生命周期阶段。我们提出的工作的最终目标是发展 一种廉价的ELQ-300前药，可以与其他抗疟疾药物在协同作用下共同配制 联合防治疟疾，支持世界范围内控制和根除疟疾的努力。 本研究的重点是ELQ-300前药与包括普罗瓜尼在内的双胍类药物的联合应用。我们寻求一种 更好地理解作为抗疟疾协同作用基础的生化机制 ELQ-300和双胍类药物。更好地理解这种相互作用将有助于设计双胍/ELQ-300 每周用于预防和治疗疟疾的人类可安全使用的前药组合。

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.