Emerging roles of oxyntomodulin-based glucagon-like peptide-1/glucagon co-agonist analogs in diabetes and obesity

Computational Peptide Design Cotargeting Glucagon and Glucagon-like Peptide-1 Receptors

“…Figure S15 shows that our designed peptide MDD GR provides an improved H-bond map compared to the WT peptides with their respective GRs. Our dual coagonist designed MDD-peptides show appreciably high agonist binding GR affinity and could in the future be tested experimentally with or without pharmacokinetic modification through fatty acid cross-linking …”

“…Our dual coagonist designed MDDpeptides show appreciably high agonist binding GR affinity and could in the future be tested experimentally with or without pharmacokinetic modification through fatty acid cross-linking. 39 3.5. Free-Energy Landscapes and Insights into the Structural Basis of GR Activation by Designed Peptide Coagonists.…”

“…In human trials, Cotadutide has been demonstrated to effectively reduce blood glucose level and body weight in treating fatty liver disease in patients with T2DM. , Despite the demonstrated promise of Cotadutide with reduced adverse effects, only monoagonist peptides targeting either GCGR or GLP-1R – but no coagonists targeting both – have been approved by the U.S. Food and Drug Administration to date. Beyond the approval of Tirzepatide cotargeting GLP-1R and GIPR, several unimolecular peptide-based coagonists are under clinical trials at the time of writing in April 2023, highlighting the clinical significance of the dual-agonist therapy for the development of bioinspired APIs for metabolic and hormonal disorders. , …”

“…Beyond the approval of Tirzepatide cotargeting GLP-1R and GIPR, 37 several unimolecular peptide-based coagonists are under clinical trials at the time of writing in April 2023, highlighting the clinical significance of the dual-agonist therapy for the development of bioinspired APIs for metabolic and hormonal disorders. 38,39 Motivated by recent experimental phage-displayed library (PDL) screens of bioactive peptides that simultaneously agonize GLP-1R and GCGR, 40 we systematically engineered peptide sequences of chimeric analogues of the endogenous peptide ligands to computationally design new peptide APIs with promising coagonist binding profiles. We benchmarked the predicted agonistic effect against the extensive PDL together with the reference endogenous peptide ligands and the experimental drug, Cotadutide.…”

“…Beyond the approval of Tirzepatide cotargeting GLP-1R and GIPR, 37 several unimolecular peptide-based coagonists are under clinical trials at the time of writing in April 2023, highlighting the clinical significance of the dual-agonist therapy for the development of bioinspired APIs for metabolic and hormonal disorders. 38 , 39 …”