Autocrine selection of a GLP-1R G-protein biased agonist with potent antidiabetic effects

Hongkai Zhang, Emmanuel Sturchler, Jiang Zhu, Ainhoa Nieto, Philip A. Cistrone, Jia Xie, LinLing He, Kyungmoo Yea, Teresa Jones, Rachel Turn, Peter S. Di Stefano, Patrick R. Griffin, Philip E. Dawson, Patricia H. McDonald () and Richard A. Lerner ()
Additional contact information
Hongkai Zhang: The Scripps Research Institute
Emmanuel Sturchler: The Scripps Research Institute
Jiang Zhu: The Scripps Research Institute
Ainhoa Nieto: The Scripps Research Institute
Philip A. Cistrone: The Scripps Research Institute
Jia Xie: The Scripps Research Institute
LinLing He: The Scripps Research Institute
Kyungmoo Yea: Shanghai Institute for Advance Immunological Studies, Shanghai Tech University
Teresa Jones: The Scripps Research Institute
Rachel Turn: The Scripps Research Institute
Peter S. Di Stefano: Zebra Biologics Inc.
Patrick R. Griffin: The Scripps Research Institute
Philip E. Dawson: The Scripps Research Institute
Patricia H. McDonald: The Scripps Research Institute
Richard A. Lerner: The Scripps Research Institute

Nature Communications, 2015, vol. 6, issue 1, 1-13

Abstract: Abstract Glucagon-like peptide-1 (GLP-1) receptor (GLP-1R) agonists have emerged as treatment options for type 2 diabetes mellitus (T2DM). GLP-1R signals through G-protein-dependent, and G-protein-independent pathways by engaging the scaffold protein β-arrestin; preferential signalling of ligands through one or the other of these branches is known as ‘ligand bias’. Here we report the discovery of the potent and selective GLP-1R G-protein-biased agonist, P5. We identified P5 in a high-throughput autocrine-based screening of large combinatorial peptide libraries, and show that P5 promotes G-protein signalling comparable to GLP-1 and Exendin-4, but exhibited a significantly reduced β-arrestin response. Preclinical studies using different mouse models of T2DM demonstrate that P5 is a weak insulin secretagogue. Nevertheless, chronic treatment of diabetic mice with P5 increased adipogenesis, reduced adipose tissue inflammation as well as hepatic steatosis and was more effective at correcting hyperglycaemia and lowering haemoglobin A1c levels than Exendin-4, suggesting that GLP-1R G-protein-biased agonists may provide a novel therapeutic approach to T2DM.

Date: 2015
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DOI: 10.1038/ncomms9918

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