The Plasmodial Surface Anion Channel And Malaria Parasite Nutrient Acquisition

2016年，Apicomplexan分子生理科研究了PSAC吸收营养和离子的分子基础，以及针对这一渠道开发抗疟疾疗法的潜力。我们先前确定，PSAC抑制剂对某些溶质的摄取效果较差。在这里，我们设计并执行了一项高通量筛选，以确定一类能够克服这种溶质-抑制剂相互作用的新型PSAC抑制剂。新的抑制剂不同于现有的阻滞剂，对通道介导的转运有明显的影响，支持通过PSAC的两条不同途径的渗透模型。针对这两种途径的抑制剂组合对体外寄生虫繁殖有很强的协同作用，而作用于单一途径的联合作用仅产生相加效应。协同作用的大小取决于外部营养浓度，这与通道在寄生虫获取营养中的重要作用一致。已确定的抑制剂将使人们能够更好地了解该通道的结构和功能，并可能成为产生协同杀寄生虫的新型组合疗法的起点。这些研究进一步证实了PSAC是抗疟疾开发的一个重要和未被探索的靶点。 PLOS One 11(2)：E0149214(2016)。

In 2016, the Apicomplexan Molecular Physiology Section examined the molecular basis of nutrient and ion uptake by PSAC and the potential for development of antimalarial therapies targeting this channel. We previously determined that PSAC inhibitors are less effective against uptake of certain solutes. Here, we designed and executed a high-throughput screen to identify a novel class of PSAC inhibitors that overcome this solute-inhibitor interaction. The new inhibitors differ from existing blockers and have distinct effects on channel-mediated transport, supporting a model of two separate routes for permeation though PSAC. Combinations of inhibitors specific for the two routes had strong synergistic action against in vitro parasite propagation, whereas combinations acting on a single route produced only additive effects. The magnitude of synergism depended on external nutrient concentrations, consistent with an essential role of the channel in parasite nutrient acquisition. The identified inhibitors will enable a better understanding of the channel's structure-function and may be starting points for novel combination therapies that produce synergistic parasite killing. These studies further validate PSAC as an essential and unexplored target for antimalarial development. PLoS ONE 11(2):e0149214 (2016).