Department of Chemistry, Syracuse University, 111 College Place, Syracuse, New York 13244, United States.
Department of Pediatrics, Seattle Children's Hospital, University of Washington, Seattle, Washington 98105, United States.
J Med Chem. 2021 Jan 28;64(2):1127-1138. doi: 10.1021/acs.jmedchem.0c01783. Epub 2021 Jan 15.
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. A novel peptide, GEP44, was obtained via receptor screens, insulin secretion in islets, stability assays, and 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.
目前迫切需要治疗肥胖和 2 型糖尿病相关合并症的疗法，理想情况下这种疗法不会引起恶心/呕吐。本研究基于胰高血糖素样肽 1 受体 (GLP-1R) 和神经肽 Y2 受体 (Y2-R) ，开发了单体肽激动剂，这些激动剂基于 exendin-4 (Ex-4) 和 PYY。通过筛选受体、胰岛胰岛素分泌、稳定性测定以及大鼠和鼩鼱的糖调节、体重减轻、恶心和呕吐研究，获得了一种新型肽 GEP44。与 Ex-4 相比，在瘦鼠和饮食诱导肥胖大鼠中，GEP44 能更显著地降低体重，而不会引起与恶心相关的行为。在鼩鼱研究中，与 Ex-4 相比，GEP44 几乎不会引起呕吐。总之，这些数据表明，用嵌合单肽靶向 GLP-1R 和 Y2-R 为开发新的糖调节治疗方法提供了一种途径，与 Ex-4 直接比较，这些治疗方法具有更好的耐受性和更显著的减重效果。
