Novel Broad-spectrum Antimalarials

新型广谱抗疟药

基本信息

批准号：
8634714
负责人：
JANE X KELLY
金额：
$ 70.33万
依托单位：
PORTLAND STATE UNIVERSITY
依托单位国家：
美国
项目类别：
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/8634714
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 novel prevent resistant strain transmission process uptake

项目摘要

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）：在当前耐药性时代，抗疟药物的选择不足。为了支持最近的根除议程，新一代化学预防性和化学治疗性抗疟药需要满足以下目标产品特征：1）针对多重耐药性疟疾的功效； 2) 对抗红细胞前寄生虫以预防感染的活性； 3) 对抗配子体的传播阻断功效； 4) 通过针对寄生虫的催眠体形式来预防复发的能力。我们发现了一种新型抗疟吖啶酮化学型，对肝期和血期疟疾具有广谱活性，也有可能有效对抗配子体和催眠子。我们在本申请中提出的工作旨在开发新型、有效、安全且廉价的抗疟药物，用于预防和治疗疟疾，从而支持在世界范围内消除该疾病。该项目的具体目标是进行先导化合物优化研究，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，并证明了增强的功效、安全性和药代动力学特征，值得进一步开发；研究对选定吖啶酮候选物的耐药倾向，并通过全基因组测序和分析确定分子靶点；并使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。