Position and Length of Fatty Acids Strongly Affect Receptor Selectivity Pattern of Human Pancreatic Polypeptide Analogues

Pancreatic polypeptide (PP) is a satiety-inducing gut hormone targeting predominantly the Y-4 receptor within the neuropeptideY 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 Yreceptors with a preference of position22 over 30 at Y-1, Y-2 and Y(5)receptors. Improved Yreceptor 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 residue30 is a promising approach for anti-obesity therapy because of maintained selectivity and a sixfold increased plasma half-life.