GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro
GLP-1-analogues resistant to degradation by dipeptidyl-peptidase IV in vitro
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DOI：
10.1016/s0167-0115(99)00095-6
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发表时间：
2000-01-29
影响因子：
--
通讯作者：
Schmidt, WE
中科院分区：
文献类型：
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作者：
Gallwitz, B;Ropeter, T;Schmidt, WE
胰高血糖素样肽-1（GLP-1）刺激胰岛素分泌，改善2型糖尿病的血糖控制。在血清中，该肽被二肽基肽酶IV（DPP IV）降解。由此产生的短生物半衰期限制了GLP-1的治疗用途。DPP IV需要GLP-1的N-末端组氨酸的完整cr-氨基以发挥其酶活性。因此，合成了以下N-末端位置1发生改变的GLP-1类似物：N-甲基化-（N-me-GLP-1）、α-甲基化（α-me-GLP-1）、脱酰胺化-（脱氨基-GLP-1）和咪唑-乳酸取代的GLP-1（imi-GLP-1）。除alpha-me-GLP-1外，所有GLP-1类似物在体外几乎不被DPP IV降解。GLP-1类似物在RINm 5 F细胞中显示出与天然GLP-1相当的受体亲和力和体外生物活性。GLP-1受体亲和力对imi-GLP-1最高，其次是alpha-me-GLP-1和N-me-GLP-1。与天然GLP-1相比，仅脱氨基GLP-1显示出15倍的受体亲和力损失。所有类似物都以与GLP-1相当的浓度刺激RINm 5 F细胞内cAMP的产生。因此，N-末端修饰可能有助于开发用于2型糖尿病治疗的长效CLP-1类似物。(C)2000 Elsevier Science B. V.保留所有权利。
Glucagon-like peptide-1 (GLP-1) stimulates insulin secretion and improves glycemic control in type 2 diabetes. In serum the peptide is degraded by dipeptidyl peptidase IV (DPP IV). The resulting short biological half-time limits the therapeutic use of GLP-1. DPP IV requires an intact cr-amino-group of the N-terminal histidine of GLP-1 in order to perform its enzymatic activity. Therefore, the following GLP-1 analogues with alterations in the N-terminal position 1 were synthesized: N-methylated-(N-me-GLP-1), alpha-methylated (alpha-me-GLP-1), desamidated-(desamino-GLP-1) and imidazole-lactic-acid substituted GLP-1 (imi-GLP-1). All GLP-1 analogues except alpha-me-GLP-1 were hardly degraded by DPP IV in vitro. The GLP-1 analogues showed receptor affinity and in vitro biological activity comparable to native GLP-1 in RINm5F cells. GLP-1 receptor affinity was highest for imi-GLP-1, followed by alpha-me-GLP-1 and N-me-GLP-1. Only desamino-GLP-1 showed a 15-fold loss of receptor affinity compared to native GLP-1. All analogues stimulated intracellular cAMP production in RINm5F cells in concentrations comparable to GLP-1. N-terminal modifications might therefore be useful in the development of long-acting CLP-1 analogues for type 2 diabetes therapy. (C) 2000 Elsevier Science B.V. All rights reserved.