Novel Broad-spectrum Antimalarials

描述（由申请人提供）：在当前的耐药性时代，抗疟药物的选择是不够的。为了支持最近的根除议程，新一代化学预防性和化学治疗性抗疟药都需要满足以下目标产品特征：1）针对多药耐药疟疾的功效; 2）针对红细胞前寄生虫的活性，以预防感染; 3）针对配子体的功效，以阻断传播; 4）通过针对寄生虫的催眠虫形式来预防复发的能力。我们已经发现了一种新的抗疟疾吖啶酮化学型，其对肝脏期和血液期疟疾具有广谱活性，并且具有对配子体和催眠体也有效的潜力。我们在这一申请中的拟议工作旨在开发新型、有效、安全和廉价的抗疟疾药物，用于预防和治疗疟疾，从而支持在世界范围内消除这种疾病。该项目的具体目标是进行先导化合物优化研究，以生产可用于全面临床前试验的候选药物，这些药物保留了广谱特征，并证明了增强的疗效、安全性和药代动力学特征，值得进一步开发;调查对选定的吖啶酮候选药物的耐药性倾向，并通过全基因组测序和分析确定分子靶点;并利用功能分析和生物分析方法探索这些广谱抗疟吖啶酮的作用模式。 公共卫生相关性：疟疾仍然是当今世界上最致命的疾病之一，由于疟原虫寄生虫的多重耐药菌株的出现和传播，情况正在恶化。每年，疟疾造成2亿至3亿临床病例，夺去100万至300万人的生命，其中大多数是5岁以下的儿童和孕妇。迫切需要预防和治疗疟疾的新的有效药物。

DESCRIPTION (provided by applicant): In the current age of drug resistance, antimalarial choices are inadequate. In order to support the recent eradication agenda, new generations of both chemoprophylactic and chemotherapeutic antimalarials need to meet the following target product profiles: 1) efficacy against multidrug-resistant malaria; 2) activity against pre- erythrocytic parasites to prevent infection; 3) efficacy against gametocytes for transmission blocking; 4) ability to prevent relapse by targeting the hypnozoite forms of the parasites. We have discovered a novel antimalarial acridone chemotype with broad- spectrum activity against both liver stage and blood stage malaria, with potential to be effective against gametocytes and hypnozoites as well. Our proposed work in this application seeks to develop novel, potent, safe, and inexpensive antimalarial drugs for both prevention and treatment of malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to conduct lead optimization studies to produce candidates for full preclinical testing that retain the broad-spectrum features and demonstrate enhanced efficacy, safety and pharmacokinetic profiles that warrant further development; to investigate the propensity for drug resistance to selected acridone candidates and identify the molecular target(s) through whole genome sequencing and analysis; and to explore mode of action(s) for these broad-spectrum antimalarial acridones using functional assays and bioanalytical approaches. PUBLIC HEALTH RELEVANCE: Malaria remains one of the deadliest diseases in the world today, and the situation is worsening due to the emergence and spread of multidrug-resistant strains of Plasmodium parasites. Each year, malaria causes 200-300 million clinical cases and claims 1-3 millions lives, mostly children under the age of five and pregnant women. There is a dire need for new and effective drugs in the prophylaxis and treatment of malaria.