Novel artemisinin derivatives for chemogenomic profiling of Plasmodium falciparum

疟疾是一种由蚊子传播的寄生虫病，是全世界的一个主要问题， 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。疟原虫 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，联合一种青蒿素衍生物（蒿甲醚、青蒿琥酯 或双氢青蒿素）与一种或两种不同的药物。大多数研究表明，ACTs仍然 有效，但部分耐药性已报告在东南亚，与寄生虫的发展， 能够在环阶段保持休眠足够长的时间，以清除青蒿素类药物， 寄生虫会重新出现目前几乎所有可用的青蒿素衍生物都是化学合成的结果。 在一些实施方案中，该化合物是在其结构上的“C-10”或碳数10（IUPAC编号）处的修饰。真菌小克银汉霉 线虫可以在7号碳原子（C7）上添加一个羟基，直到使用真菌转化， 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)制备连接有亲水基团的青蒿素的C-7衍生物和荧光探针; 2）测试那些 抗a）标准恶性疟原虫菌株（3D 7，W2 mef，HB 3）的衍生物; B）至少一种青蒿素抗性 表型（C2 A）和c）通过标准品检测可能的抗配子体作用和传递阻断活性 膜饲养试验; 3）恶性疟原虫piggyBac单插入的化学基因组学分析研究 突变体寻求更好地了解这些新的青蒿素C7衍生物与 药物靶点和途径。中心假设是没有任何空间位阻的青蒿素衍生物 过氧化物基团的阻碍将允许与细胞靶标充分相互作用，精确地标记细胞 结合到青蒿素支架上的结构并增强抑制作用。这些新的半合成 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 的过氧化物桥，预期具有增强的抗疟活性，呈现更好的药代动力学 作为阐明作用机制和耐药性的分子探针，

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.