IPSEN/Biomeasure, Inc., Milford, MA 01757, USA.
Diabetes Obes Metab. 2011 Jan;13(1):19-25. doi: 10.1111/j.1463-1326.2010.01313.x.
Glucagon-like peptide-1 (GLP-1) receptor agonists for the treatment of type 2 diabetes are administered by daily injection because of short plasma half-lives, which result partly from the biochemical instability of these peptides. There is a medical need for GLP-1 analogues that can be administered less frequently for patient convenience.
We synthesized a series of human GLP-1 (hGLP-1(7-36)NH(2) ) derivatives containing α-aminoisobutyric acid (Aib) substitutions, analysed their enzymatic stabilities and evaluated their secondary structures using circular dichroism (CD) and nuclear magnetic resonance (NMR).
Plasma stability experiments showed that only the analogue containing Aib substitutions in both the N-terminus (position 8) and the C-terminus (position 35), [Aib⁸(,)³⁵]hGLP-1(7-36)NH₂ (BIM-51077), was fully resistant to enzymatic cleavage. Incubation with human plasma kallikrein or plasmin confirmed that the Aib substitution at position 35 prevented protease cleavage around this residue, which contributes to the significantly enhanced plasma stability and increased plasma half-life. CD revealed increased C-terminal α-helicity in Aib³⁵-substituted analogues compared with both hGLP-1(7-36)NH₂ and analogues containing only Aib⁸ substitutions. Based on NMR studies, the secondary structure of BIM-51077 is similar to hGLP-1(7-36)NH₂ with a slight increase in α-helicity in the C-terminus. Compared with hGLP-1(7-36)NH₂, BIM-51077 had similar binding affinity for the human GLP-1 receptor and activated this receptor with similar potency.
We have discovered an Aib⁸(,)³⁵-substituted analogue of native hGLP-1(7-36)NH₂ (BIM-51077) that retains the structure of the native peptide, and has similar activity and enhanced stability. A sustained-release formulation of this molecule (taspoglutide) is in phase-3 clinical development.
由于胰高血糖素样肽-1（GLP-1）受体激动剂的血浆半衰期较短，部分原因是这些肽的生化不稳定性，因此需要每日注射来治疗 2 型糖尿病。对于患者而言，需要一种更方便的、能够减少注射频率的 GLP-1 类似物。
我们合成了一系列含有α-氨基异丁酸（Aib）取代的人 GLP-1（hGLP-1（7-36）NH2）衍生物，分析了它们的酶稳定性，并使用圆二色性（CD）和核磁共振（NMR）评估了它们的二级结构。
血浆稳定性实验表明，只有在 N 端（第 8 位）和 C 端（第 35 位）都含有 Aib 取代的类似物[Aib8（，）35]hGLP-1（7-36）NH2（BIM-51077）完全抵抗酶切。与人血浆激肽释放酶或纤溶酶孵育证实，第 35 位的 Aib 取代阻止了该残基周围的蛋白酶切割，这导致其显著增强的血浆稳定性和延长的血浆半衰期。CD 显示，与 hGLP-1（7-36）NH2 和仅含有 Aib8 取代的类似物相比，Aib35 取代的类似物具有增加的 C 末端α-螺旋性。基于 NMR 研究，BIM-51077 的二级结构与 hGLP-1（7-36）NH2 相似，C 末端略有增加α-螺旋性。与 hGLP-1（7-36）NH2 相比，BIM-51077 对人 GLP-1 受体具有相似的结合亲和力，并以相似的效力激活该受体。
我们发现了一种天然 hGLP-1（7-36）NH2 的 Aib8（，）35 取代类似物（BIM-51077），它保留了天然肽的结构，具有相似的活性和增强的稳定性。该分子的缓释制剂（taspoglutide）正在进行 3 期临床试验。
