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Stapled, Long-Acting Xenopus GLP-1-Based Dual GLP-1/Glucagon Receptor Agonists with Potent Therapeutic Efficacy for Metabolic Disease
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2021-07-09 , DOI: 10.1021/acs.molpharmaceut.0c00995 Chun Han 1 , Yuqing Sun 2 , Qimeng Yang 3 , Feng Zhou 3 , Xinyu Chen 3 , Lintao Wu 1 , Lidan Sun 2 , Jing Han 3
Molecular Pharmaceutics ( IF 4.9 ) Pub Date : 2021-07-09 , DOI: 10.1021/acs.molpharmaceut.0c00995 Chun Han 1 , Yuqing Sun 2 , Qimeng Yang 3 , Feng Zhou 3 , Xinyu Chen 3 , Lintao Wu 1 , Lidan Sun 2 , Jing Han 3
Affiliation
Novel peptidic glucagon receptor (GCGR) and glucagon-like peptide 1 receptor (GLP-1R) dual agonists are reported to have increased efficacy over GLP-1R monoagonists for the treatment of diabetes and obesity. We identified a novel Xenopus GLP-1-based dual GLP-1R/GCGR agonist (xGLP/GCG-13) designed with a proper activity ratio favoring the GLP-1R versus the GCGR. However, the clinical utility of xGLP/GCG-13 is limited by its short in vivo half-life. Starting from xGLP/GCG-13, dual Cys mutation was performed, followed by covalent side-chain stapling and serum albumin binder incorporation, resulting in a stabilized secondary structure, enhanced agonist potency at GLP-1R and GCGR, and improved stability. The lead peptide 2c (stapled xGLP/GCG-13 analogue with a palmitic acid albumin binder) exhibits balanced GLP-1R and GCGR activations and potent, long-lasting effects on in vivo glucose control. 2c was further explored pharmacologically in diet-induced obesity and db/db rodent models. Chronic administration of 2c potently induced body weight loss and hypoglycemic effects, improved glucose tolerance, increased energy expenditure, and normalized lipid metabolism and adiposity in relevant animal models. These results indicated that 2c has potential for development as a novel antidiabetic and/or antiobesity drug. Furthermore, we propose that the incorporation of a proper serum protein-binding motif into a di-Cys staple is an effective method for improving the stabilities and bioactivities of peptides. This approach is likely applicable to other therapeutic peptides, such as glucose-dependent insulin-tropic peptide receptor (GIPR) and GLP-1R dual agonists or GLP-1R/GCGR/GIPR triagonists.
中文翻译:
钉合、长效、基于 GLP-1/胰高血糖素受体的双重 GLP-1/胰高血糖素受体激动剂,对代谢疾病具有有效的治疗效果
据报道,新型肽类胰高血糖素受体 (GCGR) 和胰高血糖素样肽 1 受体 (GLP-1R) 双激动剂比 GLP-1R 单激动剂治疗糖尿病和肥胖症的疗效更高。我们确定了一种新型的基于爪蟾GLP-1 的双重 GLP-1R/GCGR 激动剂 (xGLP/GCG-13),其设计具有适当的活性比,有利于 GLP-1R 与 GCGR。然而,xGLP/GCG-13 的临床应用受到其体内半衰期短的限制。从 xGLP/GCG-13 开始,进行双 Cys 突变,然后进行共价侧链缝合和血清白蛋白结合剂掺入,从而形成稳定的二级结构,增强 GLP-1R 和 GCGR 的激动剂效力,并提高稳定性。先导肽2c(用棕榈酸白蛋白粘合剂钉合的 xGLP/GCG-13 类似物)表现出平衡的 GLP-1R 和 GCGR 激活以及对体内葡萄糖控制的有效、持久的影响。在饮食诱导的肥胖和db/db啮齿动物模型中进一步探索了2c的药理学。在相关动物模型中,长期服用2c可有效诱导体重减轻和降血糖作用、改善葡萄糖耐量、增加能量消耗以及使脂质代谢和肥胖正常化。这些结果表明2c具有发展为新型抗糖尿病和/或抗肥胖药物的潜力。此外,我们建议将适当的血清蛋白结合基序掺入双半胱氨酸主食是提高肽稳定性和生物活性的有效方法。这种方法可能适用于其他治疗性肽,例如葡萄糖依赖性促胰岛素肽受体 (GIPR) 和 GLP-1R 双激动剂或 GLP-1R/GCGR/GIPR 三激动剂。
更新日期:2021-08-03
中文翻译:
钉合、长效、基于 GLP-1/胰高血糖素受体的双重 GLP-1/胰高血糖素受体激动剂,对代谢疾病具有有效的治疗效果
据报道,新型肽类胰高血糖素受体 (GCGR) 和胰高血糖素样肽 1 受体 (GLP-1R) 双激动剂比 GLP-1R 单激动剂治疗糖尿病和肥胖症的疗效更高。我们确定了一种新型的基于爪蟾GLP-1 的双重 GLP-1R/GCGR 激动剂 (xGLP/GCG-13),其设计具有适当的活性比,有利于 GLP-1R 与 GCGR。然而,xGLP/GCG-13 的临床应用受到其体内半衰期短的限制。从 xGLP/GCG-13 开始,进行双 Cys 突变,然后进行共价侧链缝合和血清白蛋白结合剂掺入,从而形成稳定的二级结构,增强 GLP-1R 和 GCGR 的激动剂效力,并提高稳定性。先导肽2c(用棕榈酸白蛋白粘合剂钉合的 xGLP/GCG-13 类似物)表现出平衡的 GLP-1R 和 GCGR 激活以及对体内葡萄糖控制的有效、持久的影响。在饮食诱导的肥胖和db/db啮齿动物模型中进一步探索了2c的药理学。在相关动物模型中,长期服用2c可有效诱导体重减轻和降血糖作用、改善葡萄糖耐量、增加能量消耗以及使脂质代谢和肥胖正常化。这些结果表明2c具有发展为新型抗糖尿病和/或抗肥胖药物的潜力。此外,我们建议将适当的血清蛋白结合基序掺入双半胱氨酸主食是提高肽稳定性和生物活性的有效方法。这种方法可能适用于其他治疗性肽,例如葡萄糖依赖性促胰岛素肽受体 (GIPR) 和 GLP-1R 双激动剂或 GLP-1R/GCGR/GIPR 三激动剂。