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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：
10381572
负责人：
JANE X KELLY
金额：
$ 65.97万
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/10381572
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 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 bioluminescence imaging 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.

项目总结/文摘