Discovery of Antimalarials with Novel Mechanism of Action

疟疾仍然困扰着世界上大约一半的人口，导致大约50万人死亡，其中大部分 孩子们。疟疾在全球造成的经济损失是巨大的。目前使用的大多数药物 由于广泛出现的疟疾，用于治疗疟疾的药物正在失去效力 抗药性。即使是以青蒿素为基础的联合治疗(ACT)也是一线 在疟疾流行地区，治疗恶性疟疾的方法显示出抗药性的迹象。 东南亚。因此，迫切需要寻找作用于新靶点的新的药物先导。 开发下一代治疗疟疾的方法。我们已经筛选了 化学信息学-从生物设计库中挑选出2,115个独特的支架，该库整合了 用于抗疟原虫活动的药理上相关的天然产品的特权特征。 这个筛查已经确定了两种支架，它们表现出强大的抗疟原虫活性，作用时间较早 寄生虫的无性生命周期，包括入侵。其中一个脚手架也具有阶段V 配子体活动。拟议的研究旨在建立和进一步发展这些小说 抗疟疾的化学类型。我们假设这些化学类型将是用于 将产生有效的抗疟疾先导化合物靶向的点击到领先的优化研究 与目前的疟疾药物不同的细胞机制。实现……的目标 为了开发新的疟疾疗法并证明我们的假设，我们计划：(A)设计和 利用结构-活性和结构-性质合成早效先导化合物 关系研究。(B)确定特定阶段的作用、抗药性概况、药理学 性质、体内药代动力学、毒理学、传播阻断活性和抗疟疾 功效。(C)通过全基因组测序确定支架的分子靶点 抗性品系和化学蛋白质组学。拟议的研究具有重要意义，因为在 该项目结束时，我们希望有新的抗疟疾先导化合物与明确 作用机制。

Malaria still afflicts about half of the world population causing about 500,000 deaths, mostly children. The global economic toll of malaria is enormous. Most of the drugs that are currently utilized for malaria treatment are losing their effectiveness due to widespread emergence of drug resistance. Even artemisinin-based combination treatments (ACTs) that are the front-line therapies against falciparum malaria are showing signs of resistance in endemic regions of Southeast Asia. Therefore, it is urgent to identify new drug leads acting on novel targets for the development of next generation of therapies against malaria. We have screened cheminformatics-selected 2,115 unique scaffolds from a BioDesign library that incorporates privileged features of pharmacologically relevant natural products for antiplasmodial activities. This screen has identified two scaffolds that exhibit potent antiplasmodial activity, acting early on parasite's asexual life cycle, including invasion. One of the scaffold also possess stage V gametocyte activity. The proposed research seeks to establish and further develop these novel antimalarial chemotypes. We hypothesize that these chemotypes will be excellent platforms for hit-to-lead optimization studies that will yield effective antimalarial lead compounds targeting cellular mechanisms distinct from current malaria drugs. To accomplish the objective of developing new malaria therapeutics and prove our hypothesis, we plan to: (a) Design and synthesize early-acting lead compounds through structure-activity and structure-property relationship studies. (b) Determine stage-specific action, resistance profile, pharmacological properties, in vivo pharmacokinetics, toxicology, transmission blocking activity, and antimalarial efficacy. (c) Determine molecular targets of the scaffolds by whole genome sequencing of resistant lines and chemical proteomics. The proposed research is highly significant because at the end of the project we expect to have novel antimalarial lead compounds with defined mechanism of action.