Long-Acting GLP-1 Analogue in V-Shaped Conformation by Terminal Polylysine Modifications

作者：Yang, Xue; Li, Ying; Wang, Yuli; Zheng, Xuemin; Kong, Weiling; Meng, Fancui; Zhou, Zhixing; Liu, Changxiao; Li, Ying; Gong, Min

来源：Molecular Pharmaceutics, 2014, 11(11): 4092-4099.

DOI：10.1021/mp5002685

• GLUCAGON-LIKE PEPTIDE-1
• TYPE-2 DIABETES-MELLITUS
• CELL-PROLIFERATION
• INSULIN-SECRETION
• RECEPTOR AGONIST
• 7-36 AMIDE
• HALF-LIFE
• IN-VIVO
• LIRAGLUTIDE
• GLUCOSE

Glucagon-like peptide-1 (GLP-1) possesses multiple physiological functions, which make it a potential drug candidate for the treatment of type 2 diabetes. However, its clinical application was limited severely by its short half-life in vivo. Therefore, stabilization of GLP-1 is critical for the use of this peptide in drug development. In this study, a novel GLP-1 derivative, VGLP1K6, processed a significantly prolonged half-life in vivo. Structural analysis using molecular dynamics simulations demonstrated that VGLP1K6 has a rigid V-shaped conformation resulting from the intrapeptide disulfide bond. The C-terminal polylysine residues of VGLP1K6 caused the vulnerable N-terminus of GLP-1 (HA-fragment) to reside within the pocket-like cavity of the peptide due to the intrahydrogen bonds. The structural analysis suggested that this structural alteration contributed to the remarkable prolonged half-life of VGLP1K6, which was approximately 70 h. In addition, VGLP1K6 induced better long-acting glucose tolerance and greater HbA1c reductions than GLP-1 in rodents. Our findings suggest that the GLP-1 derivative VGLP1K6 might be a possible potent antidiabetic drug for the treatment of type 2 diabetes mellitus.

• 出版日期2014-11
• 单位天津医科大学; 天津药物研究院有限公司; 天津市环湖医院; 上海中医药大学