Mette ROSENKILDE
Professor in molecular and translational pharmacology
Department of Biomedical Sciences
Lab. For Molecular Pharmacology
Universtity of Copenhagen
Blegdamsvej 3B
DK-2200 Copenhagen
Website Mette Rosenkilde
Programm
”Drug targeting of class B1 receptors: -alone or together, -agonists or antagonists, -with or without bias”
G protein-coupled receptors (GPCR) constitute the largest family of transmembrane proteins and serve as targets for approximately 1/3 of all approved drugs. Class B1 counts 33 members, of which the glucagon-like peptide-1 receptor (GLP-1R) is a target for agonists and antagonists to control diabetes mellitus and obesity (agonists) and hypoglycemia following bariatric surgery (antagonists). GLP-1 and its sister hormone, glucose-dependent insulinotropic polypeptide (GIP), constitute the two main incretins. No drug so far has been approved for targeting the GIPR as its only target, and puzzling in vivo pharmacological results show that together with GLP-1R activation, GIPR agonism and antagonism result in the same favorable outcome on weight. Recently, the dual-agonist tirzepatide for GLP-1R and GIPR co-stimulation was approved. However, the interplay between these two receptors is still poorly understood despite the apparent advantage of targeting both receptors. The emerging field of multi-targeting ligands has also resulted in GIPR and GLP-2R dual agonists for the treatment of osteoporosis. At the molecular pharmacological level, biased agonism has been described as beneficial for multiple outcomes. From a structural point of view, bias may be built into the peptide sequences by minor, in particular, N terminal modifications. My laboratory works translationally, spanning from in vitro and in silico receptor-ligand studies over animal models to clinical studies in patients. In this talk, I will present our recent data on the pharmacological targeting of the GIP receptor, alone and with the GLP-1R or with the GLP-2R. I will also present data from our development of biased agonists for class B1 receptors focusing on physiological systems where bias seems to be a benefit. Together these data shed light on class B1 GPCRs as promising, long-sought targets for various metabolic diseases.
Host: Christian GRUBER
Contact for questions: Helmut KUBISTA