Friday, November 22, 2024
11/22/2024
PROJECT SUMMARY We propose to develop peptide ligands that bind to membrane receptors known to malfunction in maladies such as cancer and autoimmune diseases. Our preliminary data indicate that we have designed several peptide ligands that can activate or inhibit different receptors. The basis of the efficacy of the peptides is that interactions between transmembrane (TM) domains is critical for receptor function. These peptides are intended to bind to the TM domain of their target to revert defective receptor activity. Membrane insertion of the peptides is controllable, as they are triggered by environmental acidity. We will also develop a new generation of peptides where membrane insertion is triggered by an array of different stimuli. This would provide means of targeting the peptides to the desired tissues. To improve our ability to study the interactions between TM domains, we will develop a new single-molecule method that allows us to obtain stoichiometric and thermodynamic information. These studies will be complemented with investigation of how TM domains influence lipid dynamics. In addition to the development of these peptide ligands, we will perform systematic analyses to understand the molecular mechanism by which similar peptides can activate or inhibit membrane receptors. Through this work we seek to provide promising new therapeutic approaches and invaluable functional knowledge of how peptide ligands can modulate disease- causing membrane receptors.
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