Chemical Agents That Affect Biomembrane Function

University Of Notre Dame, Notre Dame IN

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Abstract

DESCRIPTION (provided by applicant): The broad, long-term objectives are to synthesize and evaluate organic molecules that can affect dynamic membrane processes such as fusion, phospholipid flip-flop, pore formation and cell surface recognition. The research is conducted for two major reasons: (a) The studies provide useful insight into the supramolecular factors that control these biomedically important processes; (b) Organic compounds are produced that can be used as reagents in membrane biology research, diagnostic indicators of disease, or as pharmaceutical leads. The specific aims of this proposal are, 1: Develop a synthetic sensor for phosphatidylserine (PS) appearance on the surface of a cell which is a hallmark of cell apoptosis. Currently, dye-labeled Annexin V is used extensively as a PS-sensing reagent that detects apoptosis, but this protein-based detection method has a number of limitations. Parallel synthesis and screening methods will be used to prepare and identify a synthetic PS-sensor that can provide a quantitative measure of apoptotic index for heterogeneous samples such as blood, spleen, lymph nodes and bone marrow. This PS-sensor could then be used to develop a clinically useful method of measuring the efficacy of anticancer drugs in individual patients. 2: Develop a synthetic PS-scramblase as a new way to help the body eliminate pathogenic cells. Parallel synthesis and screening methods will be used to identify an organic compound that can scramble the distribution of PS across plasma membranes. It is hypothesized that an increase in the concentration of externalized PS will trigger cell clearance by phagocytosis. 3: A novel prodrug strategy will selectively deliver the apoptosisinducing compound described in aim 2 to prostate cancer cells. The prodrug is activated by the prostate specific membrane antigen (PSMA) that is present in elevated amounts on the surface of prostate tumor cells. 4: Test the hypothesis that phospholipids can adopt an extended conformation (the non-polar tails extend in opposite directions) during important dynamic membrane processes such as fusion, phospholipid flip-flop, pore formation and binding of peripheral proteins. The experimental approach is to compare the supramolecular properties of conformationally restricted polar lipids that are unable to adopt a fully extended conformation with more flexible analogues that can. If the extended conformation hypothesis is confirmed then it represents a new and very different view of phospholipid dynamics.