Huang Chunhui, Palani Anandan, Yang Zhiqiang, Deng Qiaolin, Reddy Vijay, Nargund Ravi P, Lin Songnian, Altezza Simona, Bianchi Elisabetta, Orvieto Federica, Carrington Paul
Merck & Co., Inc., 33 Avenue Louis Pasteur, Boston, Massachusetts 02115, United States.
Merck & Co., Inc., 2015 Galloping Hill Road, Kenilworth, New Jersey 07033, United States.
ACS Med Chem Lett. 2022 Jul 21;13(8):1255-1261. doi: 10.1021/acsmedchemlett.2c00218. eCollection 2022 Aug 11.
The combination of insulin and incretin-based therapies has emerged as a potential promising tactic for the treatment of diabetes. Here we report the first example of a unimolecular triagonist to simultaneously target insulin, GLP-1, and glucagon receptors, aiming for better glycemic control and superior weight loss. The strategy for constructing such a unimolecular triagonist is the conjugation of the insulin moiety and GLP-1R/GCGR coagonist peptide via alkyne-azide click chemistry. Two tractable series differentiated by insulin conjugation sites, B1 and B29, were identified. Triagonist prepared through the conjugation at insulin B1 and position 24 of GLP-1R/GCGR coagonist exhibited insulin activity comparable to that of insulin degludec and potent and balanced GLP-1R and GCGR activities. Pharmacokinetic profiles of in both rat and minipig were also discussed.
胰岛素与基于肠促胰素的疗法相结合，已成为一种治疗糖尿病的潜在有效策略。在此，我们报道了首个同时靶向胰岛素、胰高血糖素样肽-1（GLP-1）和胰高血糖素受体的单分子三激动剂实例，旨在实现更好的血糖控制和更显著的体重减轻。构建这种单分子三激动剂的策略是通过炔烃-叠氮化物点击化学将胰岛素部分与GLP-1受体/胰高血糖素受体共同激动剂肽进行缀合。鉴定出了两个通过胰岛素缀合位点（B1和B29）区分的易于处理的系列。通过在胰岛素B1和GLP-1受体/胰高血糖素受体共同激动剂的24位进行缀合制备的三激动剂表现出与德谷胰岛素相当的胰岛素活性以及强效且平衡的GLP-1受体和胰高血糖素受体活性。还讨论了其在大鼠和小型猪中的药代动力学概况。
