Position and Length of Fatty Acids Strongly Affect Receptor Selectivity Pattern of Human Pancreatic Polypeptide Analogues
| Autor: | Kathrin Bellmann-Sickert, Anette Kaiser, Jens Meiler, Veronika Mäde, Annette G. Beck-Sickinger |
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| Rok vydání: | 2014 |
| Předmět: |
Molecular Sequence Data
Lipid-anchored protein Biology Ligands Pancreatic Polypeptide Biochemistry Article Residue (chemistry) Chlorocebus aethiops Drug Discovery Animals Humans Pancreatic polypeptide Amino Acid Sequence General Pharmacology Toxicology and Pharmaceutics Receptor Pharmacology chemistry.chemical_classification Fatty Acids Organic Chemistry Fatty acid Neuropeptide Y receptor Receptors Neuropeptide Y Kinetics Liver chemistry COS Cells Free fatty acid receptor Molecular Medicine Anti-Obesity Agents Half-Life Hormone |
| Zdroj: | ChemMedChem. 9:2463-2474 |
| ISSN: | 1860-7179 |
| DOI: | 10.1002/cmdc.201402235 |
| Popis: | Pancreatic polypeptide (PP) is a satiety-inducing gut hormone targeting predominantly the Y4 receptor within the neuropeptide Y multiligand/multireceptor family. Palmitoylated PP-based ligands have already been reported to exert prolonged satiety-inducing effects in animal models. Here, we suggest that other lipidation sites and different fatty acid chain lengths may affect receptor selectivity and metabolic stability. Activity tests revealed significantly enhanced potency of long fatty acid conjugates on all four Y receptors with a preference of position 22 over 30 at Y1 , Y2 and Y5 receptors. Improved Y receptor selectivity was observed for two short fatty acid analogues. Moreover, [K(30)(E-Prop)]hPP2-36 (15) displayed enhanced stability in blood plasma and liver homogenates. Thus, short chain lipidation of hPP at key residue 30 is a promising approach for anti-obesity therapy because of maintained selectivity and a sixfold increased plasma half-life. |
| Databáze: | OpenAIRE |
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