Nishizawa Naoki, Niida Ayumu, Masuda Yasushi, Kumano Satoshi, Yokoyama Kotaro, Hirabayashi Hideki, Amano Nobuyuki, Ohtaki Tetsuya, Asami Taiji
Pharmaceutical Research Division, Takeda Pharmaceutical Company, Ltd., Fujisawa 251-8555, Japan.
ACS Med Chem Lett. 2017 May 1;8(6):628-631. doi: 10.1021/acsmedchemlett.7b00047. eCollection 2017 Jun 8.
Gastrointestinal peptides such as peptide YY (PYY) can regulate appetite, which is relevant to the study of obesity. The intraperitoneal bolus administration of PYY and a 12-amino acid PYY analogue, benzoyl-[Cha,Aib]PYY (), showed similar anorectic activity by activating the Y2 receptor (Y2R). However, food intake inhibition and body weight loss were not observed upon continuous subcutaneous administration of with osmotic pumps in diet-induced obese (DIO) mice. N-Terminal elongation of , together with amino acid substitution at position 24, led to a hydrophilic 14-amino acid peptide, Ac-[d-Hyp,Cha,Aib]PYY (), that showed higher affinity and more potent agonist activity for Y2R and a robust anorectic activity with potency similar to that of PYY. In addition, the continuous subcutaneous administration of at 0.3 mg/(kg·day) induced significant body weight loss in DIO mice. These results suggest that a short-length PYY analogue can be a lead compound for antiobesity therapy in a sustained-release formulation.
诸如肽YY（PYY）之类的胃肠肽可调节食欲，这与肥胖症研究相关。腹腔推注PYY和一种12个氨基酸的PYY类似物苯甲酰基-[环己丙氨酸，α-氨基异丁酸]PYY（ ），通过激活Y2受体（Y2R）显示出相似的食欲抑制活性。然而，在饮食诱导的肥胖（DIO）小鼠中，通过渗透泵持续皮下给药 时，未观察到食物摄入抑制和体重减轻。 的N端延长，以及24位的氨基酸取代，产生了一种亲水性的14个氨基酸的肽，即乙酰基-[d-羟脯氨酸，环己丙氨酸，α-氨基异丁酸]PYY（ ），它对Y2R显示出更高的亲和力和更强的激动剂活性，并且具有与PYY相似效力的强大食欲抑制活性。此外，以0.3毫克/（千克·天）的剂量持续皮下给药 可使DIO小鼠体重显著减轻。这些结果表明，一种短长度的PYY类似物可以作为持续释放制剂中抗肥胖治疗的先导化合物。
