The Plasmodial Surface Anion Channel And Malaria Parasit

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The Apicomplexan Molecular Physiology Unit conducts basic research on the transport of ions and nutrients across various membranes of human red blood cells infected with malaria parasites. This work incorporates molecular biology and informatics, protein and lipid biochemistry, immunofluorescent localization of membrane proteins, various transport assays, biophysics, high-throughput screening of compound libraries, and examination of structure-activity relationships for small molecule inhibitors. We previously identified an unusual ion channel on human red blood cells infected with P. falciparum, which causes the deadliest form of malaria. This channel, the plasmodial surface anion channel (PSAC), is present at 1000 copies/cell, has unusual gating properties, and is permeable to a range of anions and nutrients known to be required for parasite growth. We proposed that PSAC mediates the first step in a sequential diffusive pathway of nutrient acquisition. Current projects in the lab include: 1) functional studies to examine PSAC gating and selectivity properties, 2) high-throughput screening to identify high affinity, high specificity PSAC antagonists with therapeutic potential, 3) biochemical and molecular biological studies aimed at cloning the gene(s) encoding PSAC and other transporters, and 4) heterologous expression of these transporters. Our overall goal with these projects is to probe how PSAC achieves its unusual functional properties, to understand the parasite's cell biology and physiology, and to develop new strategies for the control of malaria. In the past fiscal year, the lab made several contributions to this important field. An important advance was the execution of a high-throughput screen for PSAC antagonists. Approximately 70,000 compounds from diverse chemical libraries were screened. Novel antagonists from multiple structural classes were identified. These compounds have markedly higher affinity than previously available antagonists and are being pursued for antimalarial drug development in collaboration with the Medicines for Malaria Venture. Other important accomplishments include demonstration that PSAC is conserved in divergent malaria parasites, development of a new perfusion chamber that extends electrophysiological measurements on small cells, in vitro selection of functional mutatations in PSAC, discovery of new PSAC polymorphisms in field isolates, identification of the first PSAC agonists, cloning and heterologous expression of novel ion channel candidates from the malaria parasite, and hosting of a consensus workshop on electrophysiological measurements on infected erythrocytes.