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

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) e...

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Published inJournal 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
LanguageEnglish
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
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Abstract 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.
AbstractList 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.
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.
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.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.
Author Nim, Satra
Valiente, Pedro A.
Kim, Philip M.
Kim, Jisun
AuthorAffiliation Donnelly Centre for Cellular and Biomolecular Research
Department of Molecular Genetics
Department of Computer Science
University of Toronto
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Snippet Here, we designed three d-GLP-2 agonists that activated the glucagon-like peptide-2 receptor (GLP-2R) cyclic adenosine monophosphate (cAMP) accumulation...
Here, we designed three d -GLP-2 agonists that activated the glucagon-like peptide-2 receptor (GLP-2R) cyclic adenosine monophosphate (cAMP) accumulation...
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SubjectTerms 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
Title Computational Design of Potent and Selective d‑Peptide Agonists of the Glucagon-like Peptide‑2 Receptor
URI http://dx.doi.org/10.1021/acs.jmedchem.3c00464
https://www.ncbi.nlm.nih.gov/pubmed/37491005
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