Novel artemisinin derivatives for chemogenomic profiling of Plasmodium falciparum

用于恶性疟原虫化学基因组分析的新型青蒿素衍生物

• 批准号: 10724840
• 负责人: Paulo Batista de Carvalho
• 金额: $ 2.71万
• 依托单位: UNIVERSITY OF THE INCARNATE WORD
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-06-01 至 2024-05-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10724840
• 关键词: American; Antimalarials; Artemisinins; Binding; Biological Assay; Biological Availability; C10; Carbon; Cellular Structures; Cessation of life; Chemicals; Child; Combined Modality Therapy; Country; Cunninghamella; Derivation procedure; Development; Disease; Distant; Drug Kinetics; Drug resistance; Effectiveness; Fluorescent Probes; Future; Genes; Genomics; Genotype; Goals; Knowledge; Link; Malaria; Maps; Membrane; Metabolic Biotransformation; Metabolic Pathway; Methods; Modification; Molecular; Molecular Probes; Molecular Target; Mosquito-borne infectious disease; Parasites; Pathway interactions; Peroxides; Pharmaceutical Preparations; Phenotype; Plasmodium falciparum; Population; Predisposition; Preparation; Quantitative Reverse Transcriptase PCR; Reporting; Resistance; Side; Site; Southeastern Asia; Structure; Testing; Validation; Work; World Health Organization; analytical method; artemether; artesunate; cellular targeting; chemical synthesis; complement C2a; cost; drug resistance development; druggable target; feeding; functional group; fungus; genomic profiles; hydrophilicity; hydroxyl group; inhibitor; innovation; mutant; novel; novel therapeutics; resistance mechanism; resistant Plasmodium falciparum; resistant strain; scaffold; scale up; time use; tool; transmission blocking; treatment guidelines; virtual

Malaria, a parasitic mosquito-borne disease, is a major concern worldwide, with 219 million cases occurring in 2017 (WHO 2018 report), causing 435,000 deaths of which 61% were children under 5. Plasmodium falciparum is the causative agent of the deadliest form of malaria and current treatment guidelines include artemisinin-based combination therapies (ACTs), combining one artemisinin derivative (artemether, artesunate or dihydroartemisinin) with one or two different drugs. Most studies have demonstrated that ACTs remain effective, but partial resistance has been reported in southeast Asia, linked to the development of the parasite’s ability to remain dormant at the ring stage long enough for clearance of artemisinin-based drugs so the parasites can re-emerge. Virtually all derivatives of artemisinin currently available are the result of chemical modifications at “C-10”, or carbon number 10 on its structure (IUPAC numbering). The fungus Cunninghamella elegans can add a hydroxyl group to carbon number 7 (C7) which, until the use of fungal transformation, was inaccessible except through extensive and costly total synthesis. The overall objective for this application is to 1) prepare C-7 derivatives of artemisinin linked with hydrophilic groups and fluorescent probes; 2) test those derivatives against a) standard P. falciparum strains (3D7, W2mef, HB3); b) at least one artemisinin-resistant phenotype (C2A) and c) test for possible anti-gametocyte action and transmission blocking activity by Standard Membrane-Feeding Assay; 3) chemogenomic profiling studies of P. falciparum piggyBac single insertion mutants seeking better understanding of the interaction of these new C7 derivatives of artemisinin with druggable targets and pathways. The central hypothesis is that derivatives of artemisinin without any steric hindrance to the peroxide group will allow full interaction with cellular targets, precisely tagging cellular structures bound to the artemisinin scaffold and enhancing inhibitory effect. These new semi-synthetic derivatives of artemisinin, built for the first time using functional groups placed structurally on the opposite side of the peroxide bridge, are expected to have enhanced antimalarial activity, present better pharmacokinetic profiles and work better as molecular probes for elucidation of mechanisms of action and drug resistance.

疟疾是一种由蚊子传播的寄生性疾病，是世界范围内的一个主要问题，全球有2.19亿例疟疾病例。 2017年(世卫组织2018年报告)，造成43.5万人死亡，其中61%是5岁以下儿童。 恶性疟原虫是最致命的疟疾的病原体，目前的治疗指南包括 以青蒿素为基础的联合疗法(ACTS)，结合一种青蒿素衍生物(青蒿醚、青蒿琥酯 或双氢青蒿素)与一种或两种不同的药物。大多数研究已经证明，行为仍然存在 有效，但据报道在东南亚有部分抗药性，与寄生虫的发展有关 在环阶段保持休眠足够长的时间以清除青蒿素类药物的能力，因此 寄生虫可能会重新出现。几乎所有现有的青蒿素衍生物都是化学作用的结果。 “C-10”的修饰，或其结构上的碳数10(IUPAC编号)。真菌--坎宁汉姆氏杆菌 线虫可以在7号碳(C7)上加一个羟基，在使用真菌转化之前，7号碳是 除非通过广泛而昂贵的全合成，否则无法获得。此应用程序的总体目标是 1)制备亲水基团和荧光探针连接的青蒿素C-7衍生物；2)检测 针对a)标准恶性疟原虫菌株(3D7、W2mef、HB3)的衍生物；b)至少一种青蒿素抗药性 表型(C2a)和c)可能的抗配子体作用和传播阻断活性的标准 3)猪恶性疟原虫PiggyBac单插入片段的化学基因组图谱研究 寻求更好地了解这些新的青蒿素C7衍生物与 可下药的靶点和途径。中心假设是不含任何立体结构的青蒿素衍生物 对过氧化基的阻碍将允许与细胞靶标充分相互作用，精确标记细胞 结合青蒿素支架的结构，增强抑制作用。这些新的半合成的 青蒿素的衍生物，首次使用结构上位于相反侧的官能团构建 过氧化桥，有望增强抗疟疾活性，呈现更好的药代动力学 作为分子探针，更好地阐明作用机制和耐药性。