Pflimlin Elsa, Lear Sam, Lee Candy, Yu Shan, Zou Huafei, To Andrew, Joseph Sean, Nguyen-Tran Van, Tremblay Matthew S, Shen Weijun
Calibr at Scripps Research, 11119 North Torrey Pines Road, Suite 100, La Jolla, California 92037, United States.
ACS Med Chem Lett. 2019 Jul 5;10(8):1166-1172. doi: 10.1021/acsmedchemlett.9b00182. eCollection 2019 Aug 8.
Anorexigenic peptides offer promise as potential therapies targeting the escalating global obesity epidemic. Prolactin-releasing peptide (PrRP), a novel member of the RFamide family secreted by the hypothalamus, shows therapeutic potential by decreasing food intake and body weight in rodent models via GPR10 activation. Here we describe the design of a long-acting PrRP using our recently developed novel multiple ethylene glycol-fatty acid (MEG-FA) stapling platform. By incorporating serum albumin binding fatty acids onto a covalent side chain staple, we have generated a series of MEG-FA stapled PrRP analogs with enhanced serum stability and half-life. Our lead compound exhibits good potency and selectivity against GPR10, improved serum stability, and extended half-life (7.8 h) in mouse. Furthermore, demonstrates a potent body weight reduction effect in a diet-induced obesity (DIO) mouse model, representing a promising long-acting PrRP analog for further evaluation in the chronic obesity setting.
厌食性肽有望成为针对全球日益严重的肥胖流行问题的潜在治疗方法。催乳素释放肽（PrRP）是下丘脑分泌的RFamide家族的一个新成员，通过激活GPR10在啮齿动物模型中减少食物摄入量和体重，显示出治疗潜力。在这里，我们描述了一种长效PrRP的设计，该设计使用了我们最近开发的新型聚乙二醇 - 脂肪酸（MEG-FA）钉合平台。通过将血清白蛋白结合脂肪酸掺入共价侧链钉中，我们生成了一系列具有增强的血清稳定性和半衰期的MEG-FA钉合PrRP类似物。我们的先导化合物对GPR10表现出良好的效力和选择性，改善了血清稳定性，并在小鼠中延长了半衰期（7.8小时）。此外，在饮食诱导的肥胖（DIO）小鼠模型中显示出显著的体重减轻效果，代表了一种有前景的长效PrRP类似物，可在慢性肥胖环境中进行进一步评估。
