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Position and Length of Fatty Acids Strongly Affect Receptor Selectivity Pattern of Human Pancreatic Polypeptide Analogues
Author(s) -
Mäde Veronika,
BellmannSickert Kathrin,
Kaiser Anette,
Meiler Jens,
BeckSickinger Annette G.
Publication year - 2014
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201402235
Subject(s) - lipid anchored protein , receptor , selectivity , fatty acid , chemistry , biochemistry , potency , stereochemistry , residue (chemistry) , endocrinology , medicine , biology , in vitro , apoptosis , autophagy , catalysis
Pancreatic polypeptide (PP) is a satiety‐inducing gut hormone targeting predominantly the Y 4 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 Y 1 , Y 2 and Y 5 receptors. Improved Y receptor selectivity was observed for two short fatty acid analogues. Moreover, [K 30 (E‐Prop)]hPP 2−36 ( 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.