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Molecular principles of patho-physiological mechanisms of the incretin receptors with general implications for family B GPCRs

Subject Area Pediatric and Adolescent Medicine
Term from 2013 to 2018
Project identifier Deutsche Forschungsgemeinschaft (DFG) - Project number 231913089
 
Final Report Year 2018

Final Report Abstract

The incretin receptor GIPR and GLP-1R and the GlucR play crucial roles in glucose homeostasis. Targeting these receptors is a promising option in diabetes and obesity treatment. This project aimed on a comprehensive investigation of structural prerequisites of these class B GPCRs, the design of new compounds targeting these receptors and their testing in rodent models of obesity and disturbed glucose homeostasis as well as the elucidation of molecular insights into the function of newly designed compounds. Family B GPCRs share a high structural homology to family A GPCRs. Decisive differences include their activation by peptides bound to large extracellular domains and a different signature of preserved amino acids involved in signal transfer. To understand the specific role of peptides in receptor activation the complete binding mechanism has to be elucidated. Simulation of peptide mimicking peptides to receptors in the Hildebrand laboratory indicate a complex mechanism of recognition and binding involving all flexible extracellular parts of the receptor. A fragment based approach was developed to automatically model the conformational space of these flexible parts and integrated into a web service that promotes modeling and visualization of GPCRs. Further efforts are required to elucidate the binding mechanism of peptides and allostery of receptors. In the Tschöp part of this project a variety of compounds were designed which follow a completely new strategy: i) design of unimolecular multi-agonists engineered to simultaneously activate multiple key metabolic signaling pathways; ii) the design and preclinical evaluation of drugs engineered to deliver nuclear hormones specifically into cells expressing specific incretin hormone receptors; i.e. delivery of estrogen via GLP-1 as peptide carrier, delivery of T3 via glucagon as the peptide carrier and delivery of dexamethasone using GLP-1 as the peptide carrier. Collectively, our data demonstrate that GLP-1 based sequence hybrids with GIP or GIP/Glucagon carries a high potential to pharmacologically improve body weight and deranged glycemic control. Our chimeras between peptide hormones and nuclear hormones further demonstrate that peptide hormone selective nuclear hormone transport can be used to improve glucose and lipid metabolism without detrimental off-target effects in tissues devoid of the peptide hormone receptor. In Biebermann part of this project the elucidation of pathways induced by dual and triple agonists in addition to activation of Gs/adenylyl cyclase activation which is the main signaling pathways of class B GPCRs was performed. This pathway is seen as the major contributor to the incretin effect, however, in our part of the project we could demonstrate the multi-agonist that activate all three receptors, is capable to activate phospholipase C signaling in contrast to monoagonists and has an enhanced efficacy in action of TRPs. We conclude that this extended signaling profile of multi-agonist ligands is responsible for the superior effect on glucose homeostasis. By elucidation of the pathophysiological relevance of GIPR for glucose homeostasis we could demonstrate that variants in GIPR are unlikely to represent a frequent cause of disturbed glucose homeostasis. In sum, in this project new bioinformatics tools and compounds were designed and tested and molecular mechanisms were elucidated that are suitable for future application in patients to treat metabolic disorders.

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