Selective GLP-1 receptor antagonists and glucagon/GLP-1 co-agonists discovered through an investigation into the structure-activity relationship in glucagon-related peptides

Glucagon and glucagon-like peptide-1 (GLP-1) are two hormones of similar structure with specific receptors that signal by related biochemical mechanisms but diverge in cellular action. This doctoral thesis research has established a chemical basis for understanding how GLP-1 peptide structure relates to biochemical function, and its application to the discovery of novel ligands of unique molecular pharmacology. Through a comprehensive evaluation of GLP-1 receptor peptides, we have identified structural elements in receptor activation that differentiate agonism from antagonism. Our structure-function analysis coupled with receptor mutagenesis studies have enabled the development of a model for how two homologous hormones such as GLP-1 and its reptilian counterpart exendin-4 (Ex-4) diverge in their bioactivities. In particular, Ex-4 possesses the unique ability to be N-terminally truncated to form an antagonist and proves much more promiscuous as an agonist to N-terminal substitution. Our findings indicate that structural reinforcement of the α-helix along with enhanced contacts with the GLP-1 receptor extracellular domain can account for these differences in biochemistry. Introduction of additional chemical modification was demonstrated to prolong in vivo duration of action rendering these peptides suitable for use in chronic pharmacology studies. Our structure-function analysis also identified peptides that act as co-agonists at the GLP-1 and glucagon receptors. These observations have furthered our mechanistic knowledge of the broader subfamily of glucagon-related G protein-coupled receptor hormones.