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.