The Plasmodial Surface Anion Channel And Malaria Parasite Nutrient Acquisition

2016年，顶复合体分子生理组研究了PSAC营养和离子摄取的分子基础，以及针对该通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吸收效果较差。在这里，我们设计并执行了一个高通量筛选，以确定一类新的PSAC抑制剂，克服了溶质-抑制剂的相互作用。新的抑制剂不同于现有的阻滞剂，对通道介导的转运有不同的影响，支持通过PSAC渗透的两种不同途径的模型。两种途径特异性抑制剂的组合对寄生虫体外繁殖具有较强的协同作用，而单一途径的组合仅产生加性效应。协同作用的大小取决于外部养分浓度，这与通道在寄生虫养分获取中的重要作用一致。确定的抑制剂将使我们更好地了解该通道的结构-功能，并可能成为产生协同寄生虫杀死的新型联合疗法的起点。这些研究进一步证实PSAC是抗疟疾开发的一个重要的、尚未开发的靶点。

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).