Novel Broad-spectrum Antimalarials

描述(申请人提供)：在目前耐药的时代，抗疟疾选择不足。为了支持最近的根除议程，新一代的化学预防和化学治疗抗疟疾药物需要满足以下目标产品概况：1)对耐多药疟疾的疗效；2)对红细胞前寄生虫的活性，以防止感染；3)对配子细胞的效力，以阻断传播；4)通过靶向寄生虫的催眠体形式防止复发的能力。我们发现了一种新型的抗疟疾新药，它对肝期和血期疟疾都有广谱的活性，对配子细胞和催眠体也有潜在的作用。我们在这项申请中提出的工作旨在开发新的、有效、安全和廉价的抗疟疾药物来预防和治疗疟疾，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领先优化研究，以产生用于全面临床前试验的候选药物，这些候选药物保留了广谱药物的特征，并显示出值得进一步开发的增强的疗效、安全性和药代动力学特征；通过全基因组测序和分析，调查选定吖啶酮候选药物的耐药性倾向，并确定分子靶点(S)；以及使用功能分析和生物分析方法探索这些广谱抗疟疾吖啶类药物的作用模式(S)。

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.