Novel Broad-spectrum Antimalarials

新型广谱抗疟药

• 批准号: 8239432
• 负责人: JANE X KELLY
• 金额: $ 74.85万
• 依托单位: PORTLAND STATE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2012
• 资助国家: 美国
• 起止时间: 2012-04-01 至 2017-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8239432
• 关键词: Age; Anti-malarial drug resistance; Antimalarials; Biological Assay; Blood; Caco-2 Cells; Child; Clinical; Cytochrome P450; DNA analysis; Development; Disease; Drug Interactions; Drug Kinetics; Drug resistance; Electron Transport; Erythrocytes; Generations; Genomics; Goals; Hepatocyte; Human; Image; In Vitro; Infection; Infection prevention; Isoenzymes; Lead; Liver; Liver Microsomes; Malaria; Metabolic; Mitochondria; Modeling; Molecular; Molecular Target; Multi-Drug Resistance; Mus; Outcome; Parasite resistance; Parasites; Permeability; Pharmaceutical Preparations; Phototoxicity; Plasmodium; Plasmodium falciparum; Plasmodium vivax; Plasmodium yoelii; Preclinical Testing; Pregnant Women; Prevention; Prophylactic treatment; Relapse; Research; Resistance; Rodent; Safety; Sequence Analysis; Sporozoites; Staging; Time; Tissues; Toxic effect; Toxicity Tests; Vacuole; Validation; Work; base; chemical synthesis; cytotoxicity; genome sequencing; hemozoin; in vivo; iterative design; meetings; novel; prevent; resistant strain; transmission process; uptake

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.

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)。 与公共卫生相关：疟疾仍然是当今世界上最致命的疾病之一，由于耐多药疟原虫菌株的出现和传播，情况正在恶化。每年，疟疾造成2亿-3亿临床病例，夺走100-300万人的生命，其中大部分是五岁以下儿童和孕妇。在预防和治疗疟疾方面迫切需要新的有效药物。