Y-receptor affinity modulation by the design of pancreatic polypeptide/neuropeptide Y chimera led to Y5-receptor ligands with picomolar affinity

Abstract Neuropeptide Y (NPY) and pancreatic polypeptide (PP) bind to the Y-receptors with very different affinities: NPY has high affinity for the receptors Y 1 , Y 2 and Y 5 , while PP binds only to Y 4 -receptor with picomolar affinity. By exchanging of specific amino acid positions between the two peptides, we developed 38 full-length PP/NPY chimeras with binding properties that are completely different from those of the two native ligands. Pig NPY (pNPY) analogs containing the segment 19–23 from human PP (hPP) bound to the Y-receptors with much lower affinity than NPY itself. The affinity of the hPP analog containing the pNPY segments 1–7 and 19–23 was comparable to that of pNPY at the Y 1 - and Y 5 -receptor subtypes, and to that of hPP at the Y 4 -receptor. Furthermore, the presence of the segments 1–7 from chicken PP (cPP) and 19–23 from pNPY within the hPP sequence led to a ligand with IC 50 of 40 pM at the Y 5 -receptor. This is the most potent Y 5 -receptor ligand known so far, with 15-fold higher affinity than NPY.