Development of Potent Glucagon-like Peptide-1 Agonists with High Enzyme Stability via Introduction of Multiple Lactam Bridges
Development of Potent Glucagon-like Peptide-1 Agonists with High Enzyme Stability via Introduction of Multiple Lactam Bridges
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DOI：
10.1021/jm100602m
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发表时间：
2010-09-09
影响因子：
7.3
通讯作者：
Ahn, Jung-Mo
中科院分区：
文献类型：
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作者：
Murage, Eunice N.;Gao, Guangzu;Ahn, Jung-Mo
胰高血糖素样肽-1（GLP-1）具有降低血糖水平的能力，其调节功能使其成为治疗2型糖尿病的有吸引力的治疗剂。然而，其被酶如二肽基肽酶-IV（DPP-IV）和中性内肽酶（NEP）24.11的快速降解严重损害了其有效的临床用途。尽管已经开发了特异性DPP-IV抑制剂，但NEP 24.11靶向GLP-1序列中的多个位点，这使得其难以阻断。为了解决这一缺点，我们设计并合成了构象受限的GLP-1类似物，通过引入多个内酰胺桥，同时稳定N-和C-末端区域的α-螺旋。除了通过固定最佳受体相互作用所需的α-螺旋构象来提高受体活化能力（高达5倍）外，引入的内酰胺桥还提供了对NEP 24.11的出色屏蔽（半衰期>96 h）。这些高度受限的肽是NEP 24.1抗性GLP-1类似物的第一个例子。
Glucagon-like peptide-1 (GLP-1) has the ability to lower the blood glucose level, and its regulatory functions make it an attractive therapeutic agent for the treatment of type 2 diabetes. However, its rapid degradation by enzymes like dipeptidyl peptidase-IV (DPP-IV) and neutral endopeptidase (NEP) 24.11 severely compromises its effective clinical use. Whereas specific DPP-IV inhibitors have been developed, NEP 24.11 targets multiple sites in the GLP-1 sequence, which makes it difficult to block. To address this drawback, we have designed and synthesized conformationally constrained GLP-1 analogues by introducing multiple lactam bridges that stabilized both alpha-helices in the N- and C-terminal regions simultaneously. In addition to improving the receptor activation capability (up to 5-fold) by fixing the alpha-helical conformations required for optimal receptor interaction, the introduced lactam bridges provided outstanding shielding over NEP 24.11 (half-life of >96 h). These highly constrained peptides are the first examples of NEP 24.1-resistant GLP-1 analogues.