Novel Broad-spectrum Antimalarials

新型广谱抗疟药

• 批准号: 9031709
• 负责人: JANE X KELLY
• 金额: $ 71.51万
• 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 2018-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9031709
• 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; Genomic DNA; 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; Sporozoites; Staging; Time; Tissues; Toxic effect; Toxicity Tests; Vacuole; Validation; Work; base; chemical synthesis; cytotoxicity; genome analysis; genome sequencing; hemozoin; in vivo; iterative design; meetings; metabolic profile; novel; prevent; resistant strain; transmission process; uptake; whole genome

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.

描述（由申请人提供）：在当前的耐药时代，抗疟药的选择是不足的。为了支持最近的根除议程，新一代化学预防和化学治疗抗疟药需要满足以下目标产品特征：1)对耐多药疟疾有效；2)抗红细胞前寄生虫，预防感染；3)对配子体的传播阻断作用；4)通过靶向寄生虫的催眠子形式来防止复发的能力。我们发现了一种新的抗疟吖啶酮化学型，对肝期和血期疟疾具有广谱活性，对配子体和催眠子也有潜在的有效作用。我们在这项申请中提出的工作旨在开发新的、有效的、安全的、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优化研究，以产生用于全面临床前测试的候选药物，这些候选药物保留了广谱特征，并展示了增强的功效、安全性和药代动力学特征，值得进一步开发；通过全基因组测序和分析，探讨对选定吖啶酮候选药物的耐药倾向，并确定分子靶点；并利用功能测定和生物分析方法探索这些广谱抗疟吖啶酮的作用模式。