Novel Synergistic Antimalarials with Resistance Reversal Function

具有耐药逆转功能的新型协同抗疟药

基本信息

批准号：
10368441
负责人：
JANE X KELLY
金额：
--
依托单位：
PORTLAND VA MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-01-01 至 2025-12-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10368441
关键词：
Address Ames Assay Antimalarials Area Binding Biological Biological Assay Blood Caco-2 Cells Cardiotoxicity Chemical Exposure Complex Cytochrome P450 DNA analysis Disease Dose Drug Combinations Drug Interactions Drug Kinetics Drug Targeting Drug resistance Drug toxicity Effectiveness Environment Evaluation Fever Genomic DNA Goals Health Heme HepG2 Human In Vitro Individual Infection Isoenzymes Lead Liver Microsomes Malaria Measures Medical Metabolic Methods Military Personnel Mission Modeling Modernization Molecular Molecular Target Monitor Multi-Drug Resistance Mus Parasite resistance Parasites Permeability Personal Satisfaction Pharmaceutical Preparations Pharmacology Plasmodium Plasmodium falciparum Plasmodium yoelii Preclinical Testing Research Resistance Rodent Rodent Model Safety Salmonella typhimurium Soldier Time Toxic effect Toxicity Tests Vacuole Validation Veterans Woman Work chemical synthesis cytotoxicity design drug development genome analysis genome sequencing improved in vivo innovation iterative design lead candidate lead optimization men metabolic profile military service new combination therapies novel novel strategies operation patch clamp pre-clinical assessment pre-clinical research preclinical safety prevent programs resistant Plasmodium falciparum safety assessment single molecule synergism trait uptake whole genome

项目摘要

The global impact of malaria remains staggering despite extensive efforts to eradicate the disease. The devastating situation is largely attributed to and aggravated by the emergence and spread of multidrug- resistant Plasmodium falciparum, the cause of the deadliest form of malaria. Preventing and delaying emergence of drug-resistance is an essential goal of antimalarial drug development. Monotherapy and highly mutable drug targets have each facilitated resistance, and both are undesirable in effective long-term strategies against multi-drug resistant malaria. The novel chemotype described in this proposal represents a revolutionary approach. It specifically aims to exploit the strengths of other compounds with ideal traits by making possible a new combination therapy strategy. Our innovative design addresses an immutable parasite target and merges intrinsic potency with resistance-counteracting functions in a single molecule. It represents a novel strategy to expand, enhance, and sustain effective antimalarial drug combinations. Our proposed work in this application seeks to develop novel, potent, safe, inexpensive, and sustainable antimalarial that can be co- formulated with other antimalarials in a synergistic combination to treat malaria, thus supporting world-wide elimination of the disease. The specific goal of this project is to maximize the antimalarial potential of the dual- function acridone chemotype through structural optimization for potency, synergy, pharmacology and metabolic stability; to accomplish preclinical assessment of lead candidates that are developed through this program of research; to evaluate for safety, to investigate the mode of action(s) for these synergistic antimalarial acridones, and to explore the propensity for drug resistance to selected acridone candidates.

尽管大力消除了这种疾病，但疟疾的全球影响仍然令人震惊。这毁灭性局势在很大程度上归因于并加剧了多种危机的出现和传播抗性恶性疟原虫，是疟疾最致命形式的原因。防止和延迟抗药性的出现是抗疟药开发的基本目标。单一疗法和高度可变的药物靶标具有每个耐药性，并且在长期有效的长期有效反对多药抗性疟疾的策略。该提案中描述的新型化学型代表革命方法。它专门旨在利用其他化合物的优势，具有理想特征使新的组合疗法策略成为可能。我们的创新设计解决了一个不变的寄生虫靶标并将固有效力与单个分子中的耐药性功能合并。它代表扩展，增强和维持有效抗疟药组合的新型策略。我们提出的工作该应用程序旨在开发新颖，有效，安全，廉价和可持续的抗疟药，可以共同以协同组合以治疗疟疾的协同组合制成消除疾病。该项目的具体目标是最大化双重抗疟疾潜力功能Acridone化学型通过结构优化，用于效力，协同，药理学和代谢稳定;为通过此计划开发的主要候选人的临床前评估研究;评估安全性，以研究这些协同抗疟药的作用方式 Acridones，并探索对选定的Aclidone候选耐药性的倾向。