Quantifying Redox Potentials for Artemisinin Resistant (ARTR) Malaria

量化抗青蒿素 (ARTR) 疟疾的氧化还原电位

• 批准号: 10606620
• 负责人: PAUL D. ROEPE
• 金额: $ 19.12万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-04-08 至 2025-03-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10606620
• 关键词: Alkylation; Antimalarials; Artemisinins; Biochemical; Calibration; Carbon; Carbon Dioxide; Catabolism; Cells; Chloroquinoxaline Sulfonamide; Collection; Combined Modality Therapy; Coumarins; Data; Development; Dextrans; Drug resistance; Environment; Exposure to; Falciparum Malaria; Fluorescence; Heme; Hemoglobin; Malaria; Measures; Microscopy; Molecular; Organelles; Oxidation-Reduction; Parasite resistance; Parasites; Parents; Peptide Hydrolases; Perfusion; Pharmaceutical Preparations; Pharmacology; Phenotype; Physiologic pulse; Physiological; Plasmodium falciparum; Publishing; Resistance; Respiratory Burst; Rest; Site; Sulfhydryl Compounds; Testing; Therapeutic; Time; Vacuole; Work; adduct; artemether; benflumetol; cost effective; drug-sensitive; experimental study; fluorophore; novel; pharmacologic; resistant strain; tool

"Quantifying Redox Potentials for Artemisinin Resistant (ARTR) Malaria" Capitalizing on recent characterization of coumarin - based fluorescent GSH probes we have synthesized less expensive and more convenient probes including interesting morpholino derivatives and dextran conjugates, have characterized their GSH - dependent and other thiol - dependent fluorescence, and in proof - of - principle preliminary experiments have begun to quantify their localization and intensity within the live malarial parasite DV. We are thus uniquely able to quantify DV redox potential for ARTR (artemisinin resistant) vs ARTS (sensitive) parasites and thereby rigorously test, for the first time, the very attractive hypothesis that ferric / ferrous heme ratios may differ for DCP/ARTR parasites. This is an essential issue that further tests the predictions of the widely accepted concept that FPIX heme is the likely "activator" of ART - based drugs. Furthermore, reduced Fe2+PIX / Fe3+PIX would easily explain reduced ART drug potency in ARTR parasites. Thus, quantifying redox environment of the DV, where FPIX is released during Hb catabolism, is essential for testing particularly attractive hypotheses for ART drug pharmacology and resistance.

“量化青蒿素抗性疟疾的氧化还原潜力” 利用最近对基于香豆素的荧光GSH探针的表征，我们合成了更少的 昂贵和更方便的探针包括感兴趣的吗啉代衍生物和葡聚糖缀合物， 已经表征了它们的谷胱甘肽依赖性和其他巯基依赖性荧光，并在原理证明中 初步的实验已经开始量化它们在活的疟疾寄生虫中的定位和强度 DV。因此，我们能够独特地量化ARTR（青蒿素抗性）与ARTS的DV氧化还原电位 （敏感）寄生虫，从而严格测试，第一次，非常有吸引力的假设，铁/ DCP/ARTR寄生虫的亚铁血红素比例可能不同。这是一个基本问题，进一步考验了 预测的广泛接受的概念，FPIX血红素是可能的“激活剂”的艺术为基础的 毒品此外，降低的Fe 2 +PIX /Fe 3 +PIX将容易解释在ARTR中降低的ART药物效力。 寄生虫因此，定量DV的氧化还原环境，其中FPIX在Hb catalysts期间释放， 这对于测试ART药物药理学和耐药性的特别有吸引力的假设至关重要。