Bai Xiaohui, Niu Youhong, Zhu Jingjing, Yang An-Qi, Wu Yan-Fen, Ye Xin-Shan
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, PR China.
State Key Laboratory of Natural and Biomimetic Drugs, School of Pharmaceutical Sciences, Peking University, Xue Yuan Rd No. 38, Beijing 100191, PR China.
Bioorg Med Chem. 2016 Mar 15;24(6):1163-70. doi: 10.1016/j.bmc.2016.01.036. Epub 2016 Feb 12.
Glucagon-like peptide-1 (GLP-1) is an endogenous insulinotropic hormone with wonderful glucose-lowering activity. However, its clinical use in type II diabetes is limited due to its rapid degradation at the N-terminus by dipeptidyl peptidase IV (DPP-IV). Among the N-terminal modifications of GLP-1, backbone-based modification was rarely reported. Herein, we employed two backbone-based strategies to modify the N-terminus of tGLP-1. Firstly, the amide N-methylated analogues 2-6 were designed and synthesized to make a full screening of the N-terminal amide bonds, and the loss of GLP-1 receptor (GLP-1R) activation indicated the importance of amide H-bonds. Secondly, with retaining the N-terminal amide H-bonds, the β-peptide replacement strategy was used and analogues 7-13 were synthesized. By two rounds of screening, analogue 10 was identified. Analogue 10 greatly improved the DPP-IV resistance with maintaining good GLP-1R activation in vitro, and showed approximately a 4-fold prolonged blood glucose-lowering activity in vivo in comparison with tGLP-1. This modification strategy will benefit the development of GLP-1-based anti-diabetic drugs.
胰高血糖素样肽-1（GLP-1）是一种内源性促胰岛素激素，具有出色的降血糖活性。然而，由于其在N端被二肽基肽酶IV（DPP-IV）快速降解，其在II型糖尿病中的临床应用受到限制。在GLP-1的N端修饰中，基于主链的修饰鲜有报道。在此，我们采用两种基于主链的策略对tGLP-1的N端进行修饰。首先，设计并合成了酰胺N-甲基化类似物2-6，以全面筛选N端酰胺键，GLP-1受体（GLP-1R）激活的丧失表明酰胺氢键的重要性。其次，在保留N端酰胺氢键的情况下，采用β-肽替换策略合成了类似物7-13。通过两轮筛选，确定了类似物10。类似物10在体外维持良好的GLP-1R激活的同时，极大地提高了对DPP-IV的抗性，并且与tGLP-1相比，在体内显示出约4倍延长的降血糖活性。这种修饰策略将有利于基于GLP-1的抗糖尿病药物的开发。
