Design and Evaluation of Peptide Dual-Agonists of GLP-1 and NPY2 Receptors for Glucoregulation and Weight Loss with Mitigated Nausea and Emesis,Journal of Medicinal Chemistry

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Design and Evaluation of Peptide Dual-Agonists of GLP-1 and NPY2 Receptors for Glucoregulation and Weight Loss with Mitigated Nausea and Emesis
Journal of Medicinal Chemistry ( IF 6.8 ) Pub Date : 2021-01-15 , DOI: 10.1021/acs.jmedchem.0c01783
Brandon T Milliken ₁ , Clinton Elfers ₂ , Oleg G Chepurny ₃ , Kylie S Chichura ₁ , Ian R Sweet ₄ , Tito Borner ₅ , Matthew R Hayes ₆ , Bart C De Jonghe ₅ , George G Holz ₃ , Christian L Roth ₂ , Robert P Doyle _{1,

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Affiliation

There is a critical unmet need for therapeutics to treat the epidemic of comorbidities associated with obesity and type 2 diabetes, ideally devoid of nausea/emesis. This study developed monomeric peptide agonists of glucagon-like peptide 1 receptor (GLP-1R) and neuropeptide Y2 receptor (Y2-R) based on exendin-4 (Ex-4) and PYY_3–36. A novel peptide, GEP44, was obtained via in vitro receptor screens, insulin secretion in islets, stability assays, and in vivo rat and shrew studies of glucoregulation, weight loss, nausea, and emesis. GEP44 in lean and diet-induced obese rats produced greater reduction in body weight compared to Ex-4 without triggering nausea associated behavior. Studies in the shrew demonstrated a near absence of emesis for GEP44 in contrast to Ex-4. Collectively, these data demonstrate that targeting GLP-1R and Y2-R with chimeric single peptides offers a route to new glucoregulatory treatments that are well-tolerated and have improved weight loss when compared directly to Ex-4.

中文翻译：

GLP-1 和 NPY2 受体肽双激动剂的设计和评估，用于葡萄糖调节和减轻恶心和呕吐的体重减轻

对治疗与肥胖和 2 型糖尿病相关的合并症流行的治疗方法存在严重的未满足需求，理想情况下没有恶心/呕吐。本研究开发了基于 exendin-4 (Ex-4) 和 PYY _3–36的胰高血糖素样肽 1 受体 (GLP-1R) 和神经肽 Y2 受体 (Y2-R) 的单体肽激动剂。通过体外受体筛选、胰岛中的胰岛素分泌、稳定性测定和体内获得了一种新的肽 GEP44大鼠和鼩鼱研究葡萄糖调节、体重减轻、恶心和呕吐。与 Ex-4 相比，瘦肉和饮食诱导的肥胖大鼠中的 GEP44 使体重减轻更多，而不会引发恶心相关行为。与 Ex-4 相比，对鼩鼱的研究表明 GEP44 几乎没有呕吐。总的来说，这些数据表明，用嵌合单肽靶向 GLP-1R 和 Y2-R 为新的葡萄糖调节治疗提供了一条途径，与 Ex-4 直接相比，这些治疗具有良好的耐受性和改善的体重减轻。

更新日期：2021-01-28

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