Professor, Department of Physiology & Biophysics
Professor, Department of Medicine
Director, Medical Scientist Training Program
MALARIA PARASITE PHYSIOLOGY AND MECHANISMS OF NUCLEOSIDE AND DRUG TRANSPORT
Malaria is a major public health problem affecting large areas of the world. About 600,000 people, mostly children and pregnant woman, die each year due to malaria. Malaria is caused by unicellular parasites from the Plasmodium species that grow inside erythrocytes. Plasmodium falciparum causes the most lethal form of malaria. Plasmodium spp. parasites are purine auxotrophs and require an exogenous source of purines to survive. They import purine precursors from the host erythrocyte via equilibrative nucleoside transporters (ENTs). Knockout of PfENT1 is lethal at purine concentrations found in human plasma. This suggests that PfENT1 inhibitors might kill parasites and represent a novel target for antimalarial drug development. We seek to characterize the purine nucleoside transporters and identify inhibitors as potential antimalarial drugs. We have developed a yeast-based high throughput screen to identify PfENT1 inhibitors. We have screened a 65,000 compound library and identified 171 hits. The nine best hits block PfENT1 and kill P. falciparum parasites in culture. We are characterizing the hits and exploring the SAR for the compounds to identify more potent derivatives. Additional work is focused on testing the hits against P. vivax ENT1 and in a mouse malaria model.
NEUROTRANSMITTER-GATED ION CHANNELS: STRUCTURE, FUNCTION AND PHARMACOLOGY
Neurotransmitter-gated ion channels are essential components in synaptic transmission. They are a major target for drugs used clinically including general anesthetics. Our work focuses on the GABAA receptor, the major post-synaptic inhibitory neurotransmitter receptor in brain. It is the target for drugs used clinically in the treatment of anxiety and epilepsy, and for general anesthesia. GABAA receptors are members of a gene superfamily that includes receptors for glycine, acetylcholine, and serotonin. We seek to provide a molecular understanding of the structural bases for receptor function, modulation by drugs and cellular trafficking. This would provide a basis for rational drug design and an understanding of the molecular mechanisms by which general anesthetics function. We use a combination of techniques including site-directed mutagenesis, heterologous expression, covalent chemical modification and electrophysiology. These studies have identified the residues lining the channel, the location of channel blocker binding sites and identified conformational changes occurring during channel gating and modulation by drugs including valium and propofol.
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