UW-Madison researchers have developed a synthetic peptide through a single amino acid substitution and chemical conjugation of an aromatic molecule at the site of mutation that turns a peptide that binds one of the class B GPCRs into a dual agonist. The peptides the researchers designed bind and activate both the glucagon-like peptide-1 receptor and glucose-dependent insulintropic polypeptide receptor. This is the mechanism of activity for the recently approved obesity drug Mounjaro.
GLP-1 and GIP each contain 29 or more amino acid residues, but their sequences differ. GLP-1 does not activate the GIPR, and GIP does not activate the GLP-1R. The inventors discovered that a single change (mutation to a Lys followed by conjugation of an aromatic molecule) in the sequence of GLP-1 can “turn on” agonist activity at the GIPR. In addition, they discovered that a single change in the sequence of GIP can “turn on” agonist activity at the GLP-1R. They do observe a slight loss in affinity to the receptors for the mutant peptides as compared to the native sequence. They have in vitro data showing that the mutant peptide can bind and activate the two GPCRs.