The Plasmodial Surface Anion Channel And Malaria Parasite Nutrient Acquisition

2016年，Apicomplexan分子生理学部分研究了PSAC吸收营养和离子的分子基础，以及开发针对该通道的抗疟疗法的潜力。 我们先前确定PSAC抑制剂对某些溶质的摄取不太有效。 在这里，我们设计并执行了高通量筛选，以确定一类新的PSAC抑制剂，克服这种溶质-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。这两种途径的抑制剂的组合对体外寄生虫繁殖具有很强的协同作用，而作用于单一途径的组合仅产生累加效应。协同作用的大小取决于外部营养浓度，与寄生虫营养获取的通道的重要作用一致。所确定的抑制剂将使更好地了解通道的结构-功能，并可能是产生协同杀寄生虫的新型联合疗法的起点。 这些研究进一步验证了PSAC作为抗疟发展的一个重要和未探索的目标。 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).