Novel Broad-spectrum Antimalarials

新型广谱抗疟药

基本信息

批准号：
8447404
负责人：
JANE X KELLY
金额：
$ 66.51万
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/8447404
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 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，抗疟疾选择不足。为了支持最近的根除议程，化学预防和化学治疗抗疟药的新一代需要满足以下目标产物曲线：1）抗多药耐药疟疾的功效； 2）针对预性寄生虫的活性以防止感染； 3）针对传输阻塞的配子细胞的功效； 4）通过靶向寄生虫的催眠形式来防止复发。我们已经发现了一种新型的抗疟疾阿ac酸化学型，具有针对肝脏阶段和血液阶段疟疾的广谱活性，也有效地抵抗了配子细胞和催眠型。我们在本申请中提议的工作旨在开发新颖，有效，安全和廉价的抗疟药，以预防和治疗疟疾，从而支持全球消除该疾病。该项目的具体目标是进行铅优化研究，以生成候选临床前测试的候选，以保留广谱特征，并证明有效性，安全性和药代动力学概况有助于进一步发展；研究对选定的丙酮候选物的耐药性的倾向，并通过整个基因组测序和分析来识别分子靶标；并使用功能分析和生物分析方法来探索这些广谱抗疟疾acridones的作用方式。