Addition of a cysteine to glucagon-like peptide-1 (GLP-1) conjugates GLP-1 to albumin in serum and prolongs GLP-1 action in vivo

作者：Wu, Ye-Lin; Huang, Jing; Xu, Jin; Liu, Jian; Feng, Zhen; Wang, Yang; Lai, Yuping^*; Wu, Zi-Rong

来源：Regulatory Peptides, 2010, 164(2-3): 83-89.

DOI：10.1016/j.regpep.2010.05.003

• Glucagon-like peptide-1
• Albumin-conjugation
• Protease degradation
• Diabetic treatment

Glucagon-like peptide-1 (GLP-1) is a promising new therapeutic agent for the treatment of type 2 diabetes. However, GLP-1 has a short half-life (t(1/2)<2 min) due to rapid degradation by dipeptidyl peptidase IV in vivo. To circumvent this problem, a recombinant mGLP-1 with a cysteine at the C-terminus of GLP-1 was expressed in Escherichia coli and purified by affinity and reverse-phase chromatography. This addition of a cysteine facilitates mGLP-1 binding to serum albumin both in vitro and in vivo, thus protecting mGLP-1 from protease degradation. Similar to GLP-1, mGLP-1 stimulated CAMP production in PC12 cells and exhibited insulinotropic activity in MIN6 cells under in vitro culture conditions. Importantly, in glucose tolerance tests mice treated with mGLP-1 exhibited much lower glucose levels and much higher insulin levels versus that in mice treated with unmodified GLP-1. Furthermore, the effects of mGLP-1 on reduction of blood glucose levels lasted for 6-7 h, while the effects of unmodified GLP-1 only lasted for 0.5-1 h after injection. These results demonstrate that mGLP-1 is biologically active and its pharmaceutical efficacy is largely enhanced by the cysteine-mediated covalent conjugation with albumin in the serum after injection. Therefore, the mGLP-1 with a cysteine may be a better potential therapeutic drug than the unmodified GLP-1 for treating type 2 diabetes.

• 出版日期2010-9-24
• 单位华东师范大学