Discovery of Antimalarials with Novel Mechanism of Action

疟疾仍然困扰着大约一半的世界人口，造成大约50万人死亡，其中大多数是 孩子疟疾造成的全球经济损失是巨大的。目前大多数药物 用于疟疾治疗的药物正在失去效力， 耐药性即使是一线的青蒿素类联合疗法， 针对恶性疟疾的疗法在疟疾流行地区显示出抗药性的迹象， 东南亚因此，迫切需要鉴定作用于新靶点的新药先导物， 开发下一代疟疾疗法。我们筛选了 化学信息学从BioDesign库中选择了2，115个独特的支架， 药理学相关天然产品具有抗疟原虫活性的特权特征。 该筛选已经确定了两种具有有效抗疟原虫活性的支架， 包括入侵在内的无性生命周期。其中一个支架也具有V期 配子体活性这项研究旨在建立和进一步发展这些新的 抗疟化学型。我们假设这些化学型将是一个很好的平台， 针对先导化合物的优化研究将产生有效的抗疟先导化合物靶向 细胞机制不同于目前的疟疾药物。为了达到 开发新的疟疾疗法并证明我们的假设，我们计划：（a）设计和 通过构效和构效合成早期作用先导化合物 关系研究。(b)确定阶段特异性作用、耐药性特征、药理学 性质、体内药代动力学、毒理学、传递阻断活性和抗疟作用 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。这项研究非常重要，因为在 在项目结束时，我们预计将有新的抗疟先导化合物， 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.