Polypharmacy through Phage Display: Selection of Glucagon and GLP-1 Receptor Co-agonists from a Phage-Displayed Peptide Library
Open Access
- 12 January 2018
- journal article
- research article
- Published by Springer Science and Business Media LLC in Scientific Reports
- Vol. 8 (1), 1-9
- https://doi.org/10.1038/s41598-017-18494-5
Abstract
A promising emerging area for the treatment of obesity and diabetes is combinatorial hormone therapy, where single-molecule peptides are rationally designed to integrate the complementary actions of multiple endogenous metabolically-related hormones. We describe here a proof-of-concept study on developing unimolecular polypharmacy agents through the use of selection methods based on phage-displayed peptide libraries (PDL). Co-agonists of the glucagon (GCG) and GLP-1 receptors were identified from a PDL sequentially selected on GCGR- and GLP1R-overexpressing cells. After two or three rounds of selection, 7.5% of randomly picked clones were GLP1R/GCGR co-agonists, and a further 1.53% were agonists of a single receptor. The phages were sequenced and 35 corresponding peptides were synthesized. 18 peptides were potent co-agonists, 8 of whom showed EC50 ≤ 30 pM on each receptor, comparable to the best rationally designed co-agonists reported in the literature. Based on literature examples, two sequences were engineered to stabilize against dipeptidyl peptidase IV cleavage and prolong the in vivo half-life: the engineered peptides were comparably potent to the parent peptides on both receptors, highlighting the potential use of phage-derived peptides as therapeutic agents. The strategy described here appears of general value for the discovery of optimized polypharmacology paradigms across several metabolically-related hormones.Keywords
This publication has 54 references indexed in Scilit:
- Future directions for peptide therapeutics developmentDrug Discovery Today, 2013
- Molecular basis for negative regulation of the glucagon receptorProceedings of the National Academy of Sciences of the United States of America, 2012
- The Glucagon Receptor Is Involved in Mediating the Body Weight‐Lowering Effects of OxyntomodulinObesity, 2012
- Treatment of severe diabetic hypoglycemia with glucagon: an underutilized therapeutic approachDiabetes, Metabolic Syndrome and Obesity, 2011
- DPP‐IV‐resistant, long‐acting oxyntomodulin derivativesJournal of Peptide Science, 2011
- The metabolic actions of glucagon revisitedNature Reviews Endocrinology, 2010
- Crystal Structure of Glucagon-like Peptide-1 in Complex with the Extracellular Domain of the Glucagon-like Peptide-1 ReceptorJournal of Biological Chemistry, 2010
- Glucagon-Like Peptide 1/Glucagon Receptor Dual Agonism Reverses Obesity in MiceDiabetes, 2009
- Leptin responsiveness restored by amylin agonism in diet-induced obesity: Evidence from nonclinical and clinical studiesProceedings of the National Academy of Sciences of the United States of America, 2008
- Estimated conformation, orientation, and accumulation of dynorphin A-(1-13)-tridecapeptide on the surface of neutral lipid membranesBiochemistry, 1986