The Plasmodial Surface Anion Channel And Malaria Parasite Nutrient Acquisition

疟原虫表面阴离子通道与疟原虫营养获取

基本信息

批准号：
9354760
负责人：
SANJAY A DESAI
金额：
$ 103.18万
依托单位：
NATIONAL INSTITUTE OF ALLERGY AND INFECTIOUS DISEASES
依托单位国家：
美国
项目类别：
财政年份：
资助国家：
美国
起止时间：
至
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/9354760
关键词：
Animal Model Anions Antimalarials Basic Science Biology Cell physiology Cells Cellular biology Chemicals Combined Modality Therapy DNA Development Erythrocyte Membrane Erythrocytes Future Gene Family Genes Genetic Genetic study Goals Growth Human In Vitro Infection Informatics Ion Channel Ions Lipid Biochemistry Malaria Mediating Membrane Modeling Molecular Molecular Chaperones Molecular Genetics Molecular and Cellular Biology Multigene Family Nutrient Organism Parasites Permeability Pharmacology Physiology Plasmodium falciparum Protein Biochemistry Proteins Role Route Structure Structure-Activity Relationship Surface Transfection Transmembrane Transport Work base biophysical properties design drug development drug discovery gene cloning high throughput screening inhibitor/antagonist killings mutant novel pathogen small molecule libraries solute synergism targeted treatment uptake

项目摘要

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).

2016年，Apicomplexan分子生理科研究了PSAC的营养和离子摄取的分子基础，以及针对该通道的抗疟疾疗法的发展潜力。我们先前确定PSAC抑制剂在吸收某些溶质的情况下的有效性较小。在这里，我们设计并执行了一个高通量屏幕，以识别一种克服这种溶质抑制剂相互作用的新型PSAC抑制剂。新的抑制剂与现有阻滞剂不同，对通道介导的运输具有明显的影响，这支持了两种单独的途径，以渗透到PSAC。针对这两种途径的抑制剂组合对体外寄生虫传播具有强烈的协同作用，而作用在单个路线上的组合仅产生加性效应。协同作用的大小取决于外部营养浓度，与该通道在寄生虫营养习得中的重要作用一致。确定的抑制剂将使人们能够更好地了解通道的结构功能，并可能是产生协同寄生虫杀戮的新型组合疗法的起点。这些研究进一步验证了PSAC是抗疟发发育的必要且未开发的靶标。 PLOS ONE 11（2）：E0149214（2016）。