Potent antiobesity effect of a short-length peptide YY-analogue continuously administered in mice.

The gastrointestinal peptide, peptide YY3-36 (PYY3-36 ) and its shorter peptide analogues have been reported to reduce appetite by activating the neuropeptide Y2 receptor (Y2R), which is associated with obesity and other metabolic diseases. A 14-amino acid PYY analogue, Ac-[d-Pro24 ,Cha27,28,36 ,Aib31 ]PYY(23-36) (3), showed high binding affinity and agonist activity for the Y2R, similar to that of PYY3-36 , but had weak anorectic activity upon continuous administration in lean mice. Three amino acid substitutions [Pya(4)26 , Aib28 , Lys30 ], which contributed to the decreased hydrophobicity of 3, efficiently increased its anorectic activity. The compound containing these three amino acids, Ac-[d-Pro24 ,Pya(4)26 ,Cha27,36 ,Aib28,31 ,Lys30 ]PYY(23-36) (22), exerted more potent and durable food intake suppression than that by PYY3-36 in lean mice, as well as excellent Y2R agonist activity (EC50 : 0.20nM) and good subcutaneous bioavailability (66.6%). The 11-day continuous administration of 22 at 1mg/kg/day successfully produced antiobese and antidiabetic effects, with more than 20% body weight loss in obese and Type 2 diabetes ob/ob model mice.