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

Citations Over TimeTop 18% of 2014 papers

Abstract

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.

Related Papers

• → Converting Peptides into Drug Leads by Lipidation(2012)180 cited
• → Uncomfortably high: Testing reveals inflated THC potency on retail Cannabis labels(2023)39 cited
• → Establishment of a Potency Test by ELISA for a Rabies Vaccine for Animal Use in Japan(2003)15 cited
• → Protein Lipidation(2004)1 cited
• → Changes in the Biophysics of Lipid Memrbanes Mediated by Peptides and Drugs(2018)