Novel Modified GLP-1 Derivatives with Prolonged Glucose-Lowering Ability In Vivo
Novel Modified GLP-1 Derivatives with Prolonged Glucose-Lowering Ability In Vivo
复制标题
具有延长体内降糖能力的新型修饰 GLP-1 衍生物
DOI：
10.1007/s10989-019-09991-4
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发表时间：
2019-12
影响因子：
2.5
通讯作者：
Zhang Yunxiao
中科院分区：
文献类型：
--
作者：
Liu Yu;Wang Qing;Nie Dongsong;Zhang Yuxia;Wang Zhen;Zhang Yunxiao
二肽基肽酶-IV（DPP-IV）对天然胰高血糖素样肽1（GLP-1）的快速降解为产生抗降解GLP-1类似物提供了新的方法。GLP-1类似物与HSA的化学偶联在本研究中创新性地通过固相肽合成实现，并且在体内显示出延长的降糖能力。GLP-1（7-37）（Ala 8Aib）-Cys-HSA通过固相肽合成通过两个水平的修饰构建：Ala 8突变为氨基异丁酸（Aib）以减少DPP-IV降解，以及通过化学修饰与大血清蛋白HSA缀合以减少肾滤过。本研究采用葡萄糖耐量试验和胰岛素分泌试验检测GLP-1（7-37）（Ala 8Aib）-Cys-HSA的体内生物学活性。在T2 DM大鼠中评价了长达4周的长效降糖和胰岛素释放作用。GLP-1（7-37）（Ala 8Aib）-Cys-HSA降低正常小鼠和T2 DM大鼠的血糖。在4周的研究期间，每天两次给予T2 DM大鼠GLP-1（7-37）（Ala 8Aib）-Cys-HSA显著降低IP葡萄糖激发后的血糖波动（P < 0.01至0.05），并大大增加胰岛素分泌。这些发现表明，白蛋白缀合的GLP-1类似物模拟天然GLP-1的功能，具有延长的活性。
The rapid degradation of native glucagon-like peptide 1 (GLP-1) by dipeptidyl peptidase-IV (DPP-IV) has advanced new approaches to the generation of degradation-resistant GLP-1 analogs. Chemical coupling of GLP-1 analog to HSA is innovatively achieved by solid-phase peptide synthesis in this study and shows prolonged glucose-lowering ability in vivo. GLP-1(7-37)(Ala8Aib)-Cys-HSA was constructed by solid-phase peptide synthesis through two levels of modification: mutation of Ala8 to aminoisobutyric acid (Aib) to decrease DPP-IV degradation, and conjugation to large serum protein HSA by chemical modification to decrease renal filtration. Glucose tolerance test and insulin secretion assay were performed to examine the biological activity of GLP-1(7-37)(Ala8Aib)-Cys-HSA in vivo in the present research. Long-lasting glucose-lowering and insulin-releasing effects were evaluated up to 4 weeks in T2DM rats. GLP-1(7-37)(Ala8Aib)-Cys-HSA lowered blood glucose in normal mice and T2DM rats. Twice administration of GLP-1(7-37)(Ala8Aib)-Cys-HSA to T2DM rats daily significantly reduced glycemic excursion following IP glucose challenge (P < 0.01 to 0.05) and greatly increased insulin secretion during the 4-week study period. These findings demonstrate that the albumin-conjugated GLP-1 analog mimics the function of native GLP-1 with prolonged activity.
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DOI：
10.2146/ajhp140260
发表时间：
2015-07
期刊：
American journal of health-system pharmacy : AJHP : official journal of the American Society of Health-System Pharmacists
影响因子：
--
作者：
P. Davis;U. Ndefo;A. Oliver;E. Payton
通讯作者：
P. Davis;U. Ndefo;A. Oliver;E. Payton
影响因子：
3.1
作者：
WETTERGREN, A;SCHJOLDAGER, B;HOLST, JJ
通讯作者：
HOLST, JJ
DOI：
10.1039/c39780000537
发表时间：
1978-01-01
影响因子：
--
作者：
ATHERTON, E;FOX, H;WILLIAMS, BJ
通讯作者：
WILLIAMS, BJ
DOI：
10.1007/bf03365101
发表时间：
2007-06
期刊：
MMW - Fortschritte der Medizin
影响因子：
--
作者：
K. Parhofer
通讯作者：
K. Parhofer
影响因子：
4.8
作者：
T. Kieffer;C. Mcintosh;R. Pederson
通讯作者：
T. Kieffer;C. Mcintosh;R. Pederson