Our group is focused on the development and evaluation of polypharmacotherapies to treat obesity and diabetes. While drugs with simultaneous action on the receptors for GLP-1, GIP and glucagon are in clinical development, little is known about their specific metabolic action profile on the cellular level. Activation of GLP-1R increases cAMP via Gs signaling but also increases Ca2+ via the Gq/11 pathway and promotes ERK1/2 signaling via recruitment of ß-arrestin. Despite binding to the same receptor, different GLP-1R ligands engage selective pathways to elicit different cellular responses [1,2]. Such biased agonism is believed to have great therapeutic value because certain ligands might accentuate unique signal mechanisms that optimize therapeutic outcome. Biased agonism was demonstrated for exendin-4 and oxyntomodulin [1,2] but whether this also applies for best-in-class GLP-1-based polyagonists is unknown.
Expanding the concept of polypharmacology, we covalently linked the nuclear hormones estrogen, T3 or dexamethasone to the peptide hormones GLP-1 or glucagon [3-5]. The vison residing in this concept is that such conjugate would be internalized at only its target cell and would restrict the nuclear hormone to only enter and act on cells that express the peptide hormone receptor. While this concept is solidly confirmed in vivo, little is known about the molecular mechanisms underlying this concept on the cellular level. A solid understanding of the metabolic action profile underlying these peptide-nuclear hormone chimeras is of utmost importance to further develop this concept into novel drugs. The studies will be conducted in collaboration with Andrea Haaq at the Alberta Diabetes Institute, Canada.
Mode of action underlying best-in-class polypharmacotherapies to treat obesity and diabetes
We have recently established and will now use a variety of in vitro tools 1) to visualize internalization of these drugs, 2) to determine their action profile after being internalized (including receptor de- and resensitization, intracellular cAMP production etc.) and 3) to visualize the fate and action of the nuclear hormone cargo before and after its potential dissociation from the mother peptide. Planned experiments include in depth in vitro assessment of compound binding to the receptor, internalization, action profile after internalization, endosomal degradation and liberation, receptor de-and resensitization. Mass-spec-based phosphoproteomics will further be used to assess biased agonism properties of best in class GLP-1 mimetics and of available GLP-1-based dual- and triple agonists. The overall goal is to identify unique signaling patterns of these molecules to better understand their action and safety profile for the development of next generation pharmacotherapies.
1. Wootten et al. The Extracellular Surface of the GLP-1 Receptor Is a Molecular Trigger for Biased Agonism. Cell 2016;165:1632-1643.
2. Wootten et al. Differential activation and modulation of the glucagon-like peptide-1 receptor by small molecule ligands. Mol Pharmacol 2013;83:822-834
3. Finan et al., Targeted estrogen delivery reverses the metabolic syndrome. Nat Med 2012;18:1847-56.
4. Quarta et al., Molecular Integration of Incretin and Glucocorticoid Action Reverses
Immunometabolic Dysfunction and Obesity. Cell Metab 2017;26:620-632.e6.
5. Finan et al., Chemical Hybridization of Glucagon and Thyroid Hormone Optimizes Therapeutic Impact for Metabolic Disease. Cell 2016;167:843-857.e14.