Process specific cellular screening for antimalarial drug discovery

摘要 疟疾每年继续造成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， 风险为了使消灭疟疾运动取得成功，我们需要下一代 抗疟疾药物不仅仅是治疗疾病。一种多功能抗疟药 将能够杀死临床上沉默的肝脏阶段，启动人类 感染，以及负责传播的配子体 感染回到蚊子，除了杀死无性血液阶段， 引起疟疾。表型药物发现产生了新的候选人会议 这种非常理想的概况、靶点鉴定和表型分析已经 揭示了其中大多数消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， 并区分那些能够抑制寄生虫蛋白质合成的化合物， 在它们的原生细胞环境中运输，将加速发现新的 高价值抗疟药这种筛选方法，虽然不可知的分子 目标，将允许使用一个良好的特征化模型寄生虫，以快速识别 这些化合物具有最高的潜力，在一个多阶段抑制剂， 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.