Insertion of an N-Terminal 6-Aminohexanoic Acid after the 7 Amino Acid Position of Glucagon-Like Peptide-1 Produces a Long-Acting Hypoglycemic Agent.
Insertion of an N-Terminal 6-Aminohexanoic Acid after the 7 Amino Acid Position of Glucagon-Like Peptide-1 Produces a Long-Acting Hypoglycemic Agent.
复制标题
DOI：
10.1210/endo.142.10.8410
复制
发表时间：
2001-10
期刊：
影响因子：
4.8
通讯作者：
M. E. Doyle;N. Greig;H. Holloway;J. Betkey;M. Bernier;J. Egan
中科院分区：
文献类型：
--
作者：
M. E. Doyle;N. Greig;H. Holloway;J. Betkey;M. Bernier;J. Egan
胰高血糖素样肽-1（GLP-1）作为2型糖尿病的常规治疗方法，其生物半衰期较短，这削弱了GLP-1的使用。降解的原因是其在N-末端HAE序列处被酶二肽基肽酶IV（DPP IV）切割。为了防止DPP IV，我们研究了GLP-1类似物的生物活性，其中6-氨基己酸（Aha）插入组氨酸和丙氨酸之间的位置7和8。我们比较了这种新化合物GLP-1 Aha 8与先前描述的GLP-1 8-甘氨酸（GLP-1 Gly 8）类似物的生物活性。GLP-1 Aha 8（10 nm）在刺激RIN 1046-38细胞中胰岛素分泌方面与GLP-1（10 nm）等效。与GLP-1 Gly 8一样，在表达人GLP-1受体的完整中国仓鼠卵巢（CHO）细胞（CHO/GLP-1 R细胞）中，GLP-1 Aha 8与GLP-1受体的结合亲和力降低（IC 50：GLP-1，3.7± 0.2 nm; GLP-1 Gly 8，41 ± 9 nm; GLP-1 Aha 8，22 ± 7 nm）。GLP-1 Aha 8还显示刺激细胞内cAMP的产生。
The use of glucagon-like peptide-1 (GLP-1) as a routine treatment for type 2 diabetes mellitus is undermined by its short biological half-life. A cause of degradation is its cleavage at the N-terminal HAE sequence by the enzyme dipeptidyl peptidase IV (DPP IV). To protect from DPP IV, we have studied the biological activity of a GLP-1 analog in which 6-aminohexanoic acid (Aha) is inserted between histidine and alanine at positions 7 and 8. We have compared the biological activity of this new compound, GLP-1 Aha8, with the previously described GLP-1 8-glycine (GLP-1 Gly8) analog. GLP-1 Aha8 (10 nm) was equipotent with GLP-1 (10 nm) in stimulating insulin secretion in RIN 1046-38 cells. As with GLP-1 Gly8, the binding affinity of GLP-1 Aha8 for the GLP-1 receptor in intact Chinese hamster ovary (CHO) cells expressing the human GLP-1 receptor (CHO/GLP-1R cells) was reduced (IC50: GLP-1, 3.7± 0.2 nm; GLP-1 Gly8, 41 ± 9 nm; GLP-1 Aha8, 22 ± 7 nm). GLP-1 Aha8 was also shown to stimulate intracellular cAMP produ...