Design of Y₂ Receptor Selective and Proteolytically Stable PYY_3-36 Analogues

In recent years peptide YY (PYY) has attracted attention within the area of diabetes and obesity due to its involvement in food intake regulation and glucose homeostasis. It is well-known that PYY_1-36 is rapidly cleaved by dipeptidyl peptidase-4 to the more Y₂ receptor selective analogue PYY_3-36, which is further cleaved to the inactive analogue PYY_3-34. In order to improve the selectivity and proteolytic stability of the C-terminus, we synthesized several analogues incorporating N-methyl amino acids or β-homo amino acids and other non-natural amino acids. These were tested against all four NPY receptors, and highly potent and Y₂ receptor selective analogues were identified by combining a tryptophan residue in position 30 with either N-methyl or β-homo arginine in position 35. We also identified an analogue with a MeGln³⁴ substitution that surprisingly displayed high affinity toward all four receptors. In addition, these analogues displayed improved stability toward C-terminal proteolysis compared to native PYY_3-36.