Highly potent antiobesity effect of a short-length peptide YY analog in mice

Abstract Continuous administration of a 14-amino acid peptide YY (PYY) analog, Ac-[ d -Pro 24 ,Pya(4) 26 ,Cha 27,36 ,Aib 28,31 ,Lys 30 ]PYY(23–36) ( 4 ), which has a high binding affinity and agonist activity for the neuropeptide Y2 receptor (Y2R), has previously shown an antiobesity effect in a 2-week diet-induced obesity (DIO) study in mice. However, there remained a possibility to obtain more potent analogs by further improving its pharmacokinetic profile. A combination of the N-terminal 4-imidazolecarbonyl moiety and three amino acid substitutions, trans -4-hydroxy- d -proline ( d -Hyp) 24 , isovaline (Iva) 25 , and γ-methylleucine (γMeLeu) 28 , not only improved the binding affinity of the peptide for Y2R but also increased its anorectic activity in lean mice. In a 2-week DIO study in mice, continuous administration of 4-imidazolecarbonyl-[ d -Hyp 24 ,Iva 25 ,Pya(4) 26 ,Cha 27,36 ,γMeLeu 28 ,Lys 30 ,Aib 31 ]PYY(23–36) ( 31 , PYY-1119) at a dose of 0.03 mg/kg/day showed a highly potent antiobesity effect, with more than 10% body weight reduction.