Backbone modification of glucagon-like peptide-1 (GLP-1) to alter signaling at the GLP-1 receptor

Structural variation of peptide hormones has been widely practiced to try to elucidate relationships between peptide structure and function, but these studies have focused almost exclusively on amino acid side-chain modification. Backbone modification is an alternative approach to structural variation of peptides and can generate unique and useful biological activity profiles. One strategy to modify a peptide backbone involves replacing selected alpha-amino acid residues with beta-amino acid residues, yielding an "alpha/beta-peptide." alpha/beta-Peptides offer enhanced resistance to proteolysis relative to their ?-peptide counterparts, which can lead to favorable properties in vivo. In addition, alpha/beta-peptides can mimic overall alpha-helical structure while subtly altering side chain arrangement, which can cause changes in peptide-based signaling. The research presented in this thesis is focused on evaluating the effects of backbone modifications on complex signaling responses. Ultimately, the functional impact of backbone modification might lead to hormone analogues that display unique and beneficial properties relative to the alpha-peptide parent. To test the utility of backbone modifications, I have focused on the glucagon-like peptide-1 receptor (GLP-1R), which is activated by the polypeptide hormone GLP-1. The GLP-1R is expressed on the surface of pancreatic beta-cells, which regulate blood glucose in response to many different stimuli, including GLP-1. Activation of the GLP-1R by GLP-1 promotes glucose-stimulated insulin secretion and subsequent clearance of glucose from the blood. In addition, GLP-1R stimulation is important for proper beta-cell function. My graduate research has focused on developing alpha/beta-peptide analogues of GLP-1 for use as tools to probe the impact of various GLP-1R-mediated signaling pathways on beta-cell activity. My results demonstrate that selective incorporation of beta-amino acid residues into the helical region of GLP-1 can alter the conformational preferences of the GLP-1R to favor activation of a subset of pathways relative to the pathways activated by GLP-1. In addition, highly potent alpha/beta-peptides display enhanced stability and prolonged signaling relative to GLP-1, which may be useful in various biomedical settings.