Research in the Seyfang laboratory focuses on two major projects (i) membrane permeases (transporters) as target for drug delivery and (ii) cytochrome b5 reductase as enzymatic drug target in opportunistic microbial pathogens including protozoan parasites and nosocomial and neuro-pathogenic fungi.
We are studying membrane permeases (transporters) and receptors in opportunistic microbial pathogens including protozoan parasites (trypanosomes, Leishmania) and nosocomial and neuro-pathogenic fungi (Candida albicans, Cryptococcus neoformans). We use a multi-disciplinary approach of biochemistry, proteomics, molecular pharmacology and genetics to investigate the structure-function relationship, substrate/drug selectivity, protein-protein interaction, and significance for microbial pathogenicity of these membrane proteins at the molecular level in both in vitro culture and animal models. The objective of this project is to use membrane permeases, such as the myo-inositol transporter MIT, for delivery of cytotoxic and parasite-specific substrate analogues as novel pharmacological targets in these microbial pathogens.
A second project investigates cytochrome b5 reductase as enzymatic drug target in these opportunistic pathogens. Cytochrome b5 reductase (Cb5r) plays an important role in P450-mediated detoxification of xenobiotics and drugs, lipid biosynthesis, and the synthesis of cholesterol (humans, Leishmania) or ergosterol (fungi and Trypanosoma cruzi). Hence we use recombinant Cb5r protein for biochemical, structural and pharmacological studies and in silico modeling as a novel pharmacological target in these opportunistic microbial pathogens.
TECHNIQUES that are applied in the laboratory include protein biochemistry and proteomics, microarray and real-time PCR gene expression analysis, site-directed mutagenesis, targeted gene disruption and reverse genetics, heterologeous expression in Xenopus oocytes microinjected with transporter RNA, and the generation of transgenic protozoa and candida cells. Furthermore, we use axenic cultivation of both mammalian and insect forms of trypanosomes and Leishmania, and candida (yeast and hyphae forms) to probe the pharmacology of these important permeases in vivo. Hence, our studies are aimed to develop novel inositol-based drugs such as fluoro-inositol analogues specific for these microbial pathogens.
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