Process specific cellular screening for antimalarial drug discovery

摘要 疟疾每年继续导致40多万人死亡， 对一线药物的耐药性的发展和传播将使更多的人丧生 风险。为使根除疟疾运动取得成功，我们需要下一代 不仅仅是治疗疾病的抗疟疾药物。一种多功能的抗疟疾药 将能够杀死临床上沉默的肝脏阶段，这一阶段启动了人类 感染，以及负责传播的配子体 感染回蚊子，除了杀死无性繁殖的血液阶段， 导致疟疾。表型药物发现产生了新的候选人会议 这种非常令人满意的特征，以及目标识别和表型特征描述 揭示了其中的大多数都废除了蛋白质的核心寄生过程 生产和运输。开发特定于流程的屏幕以确定 并区分那些能够抑制寄生虫蛋白质合成和 在其原生细胞环境中的运输，将加速发现新的 高价值的抗疟疾药。这种筛选方法，虽然对分子不可知 目标，将允许使用特征良好的模型寄生虫来快速识别 那些最有可能成为多阶段抑制剂的化合物 单一主屏幕。

Abstract Malaria continues to kill upwards of 400,000 people annually, and the development and spread of resistance to frontline drugs will put more lives at risk. For the malaria eradication campaign to succeed, we need next generation antimalarial drugs that do more than just treat disease. A versatile antimalarial would be capable of killing the clinically silent liver stage that initiates human infection, as well as the gametocytes which are responsible for transmitting infection back to mosquitos, in addition to killing the asexual blood stages that cause malaria. Phenotypic drug discovery has yielded new candidates meeting this highly desirable profile, and target identification and phenotypic profiiing have revealed that most of these abrogate the core parasite processes of protein production and transport. Development of process-specific screens to identify and differentiate those compounds able inhibit parasite protein synthesis and transport in their native cellular context, would accelerate the discovery of new high value antimalarials. This screening approach, while agnostic to molecular target, will allow use of a well-characterized model parasite to rapidly identify those compounds with the highest potential for being multistage inhibitors in a single primary screen.