Second-Generation Novel Liver Stage Active Antimalarials

第二代新型肝期活性抗疟药

基本信息

批准号：
10180516
负责人：
JANE X KELLY
金额：
$ 68.15万
依托单位：
PORTLAND STATE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2026-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10180516
关键词：
Age Antimalarials Biological Assay Blood Caco-2 Cells Cessation of life Child Clinical Cytochrome P450 DNA analysis Development Disease Dose Drug Interactions Drug Kinetics Drug resistance Electron Transport Erythrocytes Generations Genomic DNA Glucosephosphate Dehydrogenase Deficiency Goals Hepatocyte Human Image In Vitro Individual Infection Isoenzymes Lead Liver Liver Microsomes Malaria Metabolic Mitochondria Modeling Molecular Molecular Target Mus Parasite resistance Parasites Patients Permeability Pharmaceutical Preparations Plasmodium Plasmodium berghei Plasmodium falciparum Plasmodium yoelii Preclinical Testing Pregnant Women Prevention Relapse Research Resistance Rodent Rodent Model Safety Series Solubility Sporozoites Time Toxic effect Toxicity Tests Validation Vulnerable Populations chemical synthesis combat cytotoxicity genome analysis genome sequencing in vivo iterative design lead candidate lead optimization malaria infection metabolic profile nonhuman primate novel preclinical development preclinical evaluation preclinical safety prevent process optimization safety assessment tool vaccine access whole genome

项目摘要

PROJECT SUMMARY/ABSTRACT The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. We have developed a novel antimalarial acridone chemotype with dual stage efficacy against both liver stage and blood stage malaria, as well as single-dose cure ability and potential to prevent relapsing infection. The ability to combat multiple stages of the infection represents a powerful tool, and one ideally suited to achieve the broadest possible benefit as the malaria eradication effort proceeds. A rigorous optimization process has produced a series of second-generation acridones with significant improvements in efficacy, metabolic stability, pharmacokinetics, and safety profiles. Our overarching goal is to develop a novel antimalarial that is safe in individuals with G6PD deficiency, and in the most vulnerable populations – pregnant women and children, thus supporting world-wide elimination of the disease. The specific goal of this project is to conduct lead optimization studies to produce second-generation candidates for full preclinical evaluation that retain the broad-spectrum features and demonstrate enhanced efficacy, safety, solubility, and metabolic/pharmacokinetic profiles; 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(s) of action for these liver stage active antimalarial acridones using functional assays and bioanalytical approaches.

项目摘要/摘要疟疾的全球影响仍然令人震惊的目的地，以消除这种疾病。我们已经开发了一种新型的抗疟疾阿丝酮化学型，具有双阶段效率，均针对肝脏阶段和血液阶段疟疾以及单剂量治疗能力和防止感染复发的潜力。能力与感染的多个阶段作斗争代表了一个强大的工具，一种理想的工具适合实现随着疟疾根除努力的进行，最广泛的可能收益。严格的优化过程具有产生了一系列的第二代acridone，具有显着提高效率，代谢稳定性，药代动力学和安全概况。我们的总体目标是开发一种安全的抗疟药患有G6PD缺乏症的人，在最脆弱的人群中 - 孕妇和儿童，因此支持全世界消除该疾病。该项目的具体目标是进行铅优化研究以生产第二代候选人进行全面临床前评估，以保留广谱特征，并展示提高效率，安全性，可溶性和代谢动力学概况；调查对选定的Acridone候选耐药性的承诺，并确定分子靶标通过整个基因组测序和分析；并探索这些动作模式使用功能测定和生物分析方法的肝脏活性抗疟疾抗氨基酸。