Computational Design of Potent and Selective d‑Peptide Agonists of the Glucagon-like Peptide‑2 Receptor

• Published in: Journal of medicinal chemistry Vol. 66; no. 15; pp. 10342 - 10353
• Main Authors: Valiente, Pedro A., Nim, Satra, Kim, Jisun, Kim, Philip M.
• Format: Journal Article
• Language: English
• Published: United States American Chemical Society 10.08.2023
• Subjects: Cyclic AMP - metabolism; Glucagon-Like Peptide 2; Glucagon-Like Peptide-1 Receptor - agonists; Glucagon-Like Peptide-2 Receptor; Peptides - pharmacology; Phosphorylation; Proto-Oncogene Proteins c-akt - metabolism
• ISSN: 0022-2623; 1520-4804; 1520-4804
• DOI: 10.1021/acs.jmedchem.3c00464

Here, we designed three d-GLP-2 agonists that activated the glucagon-like peptide-2 receptor (GLP-2R) cyclic adenosine monophosphate (cAMP) accumulation without stimulating the glucagon-like peptide-1 receptor (GLP-1R). All the d-GLP-2 agonists increased the protein kinase B phosphorylated (p-AKT) expression levels in a time- and concentration-dependent manner in vitro. The most effective d-GLP-2 analogue boosted the AKT phosphorylation 2.28 times more effectively compared to the native l-GLP-2. The enhancement in the p-AKT levels induced by the d-GLP-2 analogues could be explained by GLP-2R’s more prolonged activation, given that the d-GLP-2 analogues induce a lower β-arrestin recruitment. The higher stability to protease degradation of our d-GLP-2 agonists helps us envision their potential applications in enhancing intestinal absorption and treating inflammatory bowel illness while lowering the high dosage required by the current treatments.