Discovery of Novel, Potent and Long Acting CCK Analogs

Hunter, Robert G.; Carpenter, Andrew J.; Swiger, Erin; Mebrahtu, Makda; Wiard, Robert P.; Acker, Andrea; Roller, Shane; Paulik, Mark; Srivastava, Ved

doi:10.17952/24aps.2015.195

Cited by 2 publications

(2 citation statements)

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“…It is therefore very likely that any degradation product or metabolite formed from a CCK peptide containing DMeAsp-MePhe at the C-terminus would be either CCK-1R selective or inactive. In the literature, CCK-1R selectivity of CCKR agonist peptides has been achieved typically by using 32-MeAsp , or Lys(Tac) in position 31. ,,, The use of 32-DMeAsp for this purpose seems to have remained largely unknown, although one such compound ( 2 ) including solid biological data was published in 1997 by Pierson et al In Pierson’s study, peptide 2 decreased food intake less potently than its 32-MeAsp isomer ARR15849 in dogs after intranasal administration and was therefore deselected, which explains the lack of later attention for this compound. The reported relatively lower anorectic potency of peptide 2 in dogs might be due to a possibly higher clearance of peptide 2 compared to its 32-MeAsp isomer, in line with our pig PK data for 32-DMeAsp compound 9 and its MeAsp isomer 8 .…”

Section: Discussion and Conclusionmentioning

confidence: 99%

Structure–Activity Relationships and Characterization of Highly Selective, Long-Acting, Peptide-Based Cholecystokinin 1 Receptor Agonists

et al. 2019

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A group of peptide-based, long-acting, stable, highly selective cholecystokinin 1 receptor (CCK-1R) agonists with the potential to treat obesity has been identified and characterized, based on systematic investigation of synthetic CCK-8 analogues with N-terminal linkage to fatty acids. Sulfated Tyr in such compounds was stable in neutral buffer. CCK-1R selectivity was achieved mostly by introducing d-N-methyl-Asp instead of Asp at the penultimate position of CCK-8. Our compound 9 (NN9056) showed similar in vitro CCK-1R potency and CCK-1R affinity as CCK-8, very high selectivity for CCK-1R over the cholecystokinin 2 receptor (CCK-2R), strong reduction of food intake in lean pigs for up to 48 h after one subcutaneous injection without adverse effects, a plasma half-life of 113 h in minipigs after intravenous injection, and acceptable chemical stability in a neutral liquid formulation. In addition, we found a highly selective CCK-2R agonist by replacing Gly in a CCK-8 derivative with Glu.

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Section: Discussion and Conclusionmentioning

confidence: 99%

Structure–Activity Relationships and Characterization of Highly Selective, Long-Acting, Peptide-Based Cholecystokinin 1 Receptor Agonists

et al. 2019

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“…54 Research has focused on an intra-islet loop based on local islet secretion of these peptides, whether GLP-1 and CCK originating from the gut have the same islet effects is unknown. Sulphation of CCK at a tyrosine located 7 residues from the C-terminus is crucial for CCK bioactivity, 55 this post-translational modification allows for strengthened protein-protein interaction. 56 Glucagon-like peptide-1 secreted from the α-cell targets the β-cell to stimulate CCK production, while CCK can also stimulate α-cells to release GLP-1 increasing β-cell survival and proliferation, in a positive feedback loop within β-cells.…”

Section: Nonclassical Islet Peptides – Pancreatic Effectsmentioning

confidence: 99%

Nonclassical Islet Peptides: Pancreatic and Extrapancreatic Actions

English

Irwin

2019

Clin Med Insights Endocrinol Diabetes

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The pancreas has physiologically important endocrine and exocrine functions; secreting enzymes into the small intestine to aid digestion and releasing multiple peptide hormones via the islets of Langerhans to regulate glucose metabolism, respectively. Insulin and glucagon, in combination with ghrelin, pancreatic polypeptide and somatostatin, are the main classical islet peptides critical for the maintenance of blood glucose. However, pancreatic islets also synthesis numerous 'nonclassical' peptides that have recently been demonstrated to exert fundamental effects on overall islet function and metabolism. As such, insights into the physiological relevance of these nonclassical peptides have shown impact on glucose metabolism, insulin action, cell survival, weight loss, and energy expenditure. This review will focus on the role of individual nonclassical islet peptides to stimulate pancreatic islet secretions as well as regulate metabolism. In addition, the more recognised actions of these peptides on satiety and energy regulation will also be considered. Furthermore, recent advances in the field of peptide therapeutics and obesity-diabetes have focused on the benefits of simultaneously targeting several hormone receptor signalling cascades. The potential for nonclassical islet hormones within such combinational approaches will also be discussed.

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Discovery of Novel, Potent and Long Acting CCK Analogs

Cited by 2 publications

References 4 publications

Structure–Activity Relationships and Characterization of Highly Selective, Long-Acting, Peptide-Based Cholecystokinin 1 Receptor Agonists

Structure–Activity Relationships and Characterization of Highly Selective, Long-Acting, Peptide-Based Cholecystokinin 1 Receptor Agonists

Nonclassical Islet Peptides: Pancreatic and Extrapancreatic Actions

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