Artemisinin activation in artemisinin resistant malarial parasites

青蒿素对青蒿素耐药的疟疾寄生虫的激活

• 批准号: 9978323
• 负责人: PAUL D. ROEPE
• 金额: $ 22.84万
• 依托单位: GEORGETOWN UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-03-01 至 2022-02-28
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9978323
• 关键词: Antimalarials; Artemisinins; Arts; Clinic; Clinical; Collection; Combined Modality Therapy; Data; Drug resistance; Evolution; Falciparum Malaria; Far East; Fractionation; Genes; Genetic Determinism; Heme; In Vitro; Infectious Diseases Research; Kinetics; Malaria; Methods; Molecular; Mutation; Parasite resistance; Parasites; Pharmaceutical Preparations; Pharmacology; Phenotype; Plasmodium falciparum; Recording of previous events; Research Personnel; Resistance; Resistance profile; Role; Severities; Techniques; Testing; Time; Work; adduct; artemether; artesunate; base; chemotherapy; effective therapy; experimental study; in vivo; liquid chromatography mass spectrometry; metabolomics; novel; quinoline; resistant strain; reverse genetics

Currently artemisinin (ART) combination therapies (ACTs) are the only universally effective treatments vs all malaria worldwide. Troublingly however, a harbinger of ART drug resistance (ArtR) has emerged in South East Asia, referred to as the "delayed clearance phenotype" (DCP). Elucidation of the molecular mechanism of DCP/ArtR is one of the most pressing issues in infectious disease research today. Multiple genetic determinants have been described for DCP, with the most common being mutations in the PfK13 gene, but currently no single unifying molecular mechanism for DCP is known. Our group has been the first to apply targeted metabolomics to the analysis of ART drug pharmacology and ArtR. In essence our malarial parasite culture, fractionation, and extraction methods, combined with liquid chromatography - mass spectrometry (LCMS) techniques, have allowed us to quantify, for the first time, ART drug - FPIX heme covalent adducts formed within live malarial parasites. Our hypothesis is that ART drug - FPIX heme adduct formation correlates with ArtR, and that adduct abundance predicts the severity of ArtR ("fold" ArtR). We will use these newly perfected methods to test the attractive hypothesis that adduct abundance is correlated with the degree of severity of evolving ArtR. Our work will be comprehensive and span analysis of adducts formed vs multiple natural and synthetic ART drugs and ACT combinations, as well as multiple types of ArtR parasites that harbor all common PfK13 mutations or that do not appear to harbor PfK13 mutations at all.

目前，青蒿素(ART)联合疗法(ACTs)是唯一一种普遍有效的疗法。 治疗方案VS全球所有疟疾。然而，令人不安的是，抗逆转录病毒耐药(ART R)的先兆 出现在东南亚，称为“延迟清除表型”(DCP)。澄清： DCP/ArtR的分子机制是当今传染病研究中最紧迫的问题之一。 已有多个基因决定因素被描述为DCP，其中最常见的是 PfK13基因，但目前尚不清楚DCP的单一统一分子机制。我们的团队已经 首次将靶向代谢组学应用于抗逆转录病毒药物、药理学和抗逆转录病毒受体的分析。本质上是 我们的疟疾寄生虫培养、分离和提取方法，结合高效液相色谱- 质谱学(LCMS)技术，使我们能够首次对抗逆转录病毒药物--FPIX进行定量 在活的疟疾寄生虫中形成的血红素共价加合物。我们的假设是抗逆转录病毒药物-FPIX 血红素加合物的形成与ArtR相关，而加合物的丰度预示着ArtR的严重程度(“折叠” ArtR)。我们将使用这些新完善的方法来检验加合丰度是 与进展中的ART的严重程度相关。我们的工作将是全面和跨度的分析 形成的加合物与多种天然和合成ART药物和ACT组合以及多种 含有所有常见PfK13突变或似乎不含有PfK13的ArtR寄生虫类型 根本就没有突变。