GLP-1 Val8: A Biased GLP-1R Agonist with Altered Binding Kinetics and Impaired Release of Pancreatic Hormones in Rats

• DOI: 10.1021/acsptsci.0c00193
• Publication Date: 2021-01-19T18:35:53Z
• Authors: Wijnand J. C. van...; Florent X. Smit; Charlotte B. Chri...; Thor C. Møller; Gertrud M. Hjortø; Olav Larsen; Sine P. Schiellerup; Hans Bräuner-Osborne; Jens J. Holst; Bolette Hartmann; Thomas M. Frimurer; Mette M. Rosenkilde
• Keywords: Internalization; Incretin

Biased ligands that selectively confer activity in one pathway over another are pharmacologically important because biased signaling may reduce on-target side effects and improve drug efficacy. Here, we describe an N-terminal modification the incretin hormone glucagon-like peptide (GLP-1) alters capabilities of GLP-1 receptor (GLP-1R) by making it G protein internalization but was originally designed to DPP-4 resistance thereby prolong half-life GLP-1. Despite similar binding affinity, cAMP production, calcium mobilization, substitution a single amino acid (Ala8 Val8) N-terminus GLP-1(7-36)NH2 (GLP-1 severely impaired its ability internalize GLP-1R compared endogenous In-depth kinetics analyses revealed shorter residence time for Val8 as well slower observed association rate. Molecular dynamics (MD) displayed weaker less interactions with GLP-1R, distinct conformational changes In vitro validation MD, alanine substitutions, confirmed stronger impairments Val8-mediated perfused rat pancreas, acute stimulation resulted lower insulin somatostatin secretion Our study illustrates profound differences molecular pharmacological properties, which essential therapeutic targeting system, can be induced subtle This information could facilitate development optimized agonists.