Stability and Bioactivity Studies on Dipeptidyl Peptidase IV Resistant Glucogan-like Peptide-1 Analogues

Title: Stability and Bioactivity Studies on Dipeptidyl Peptidase IV Resistant Glucogan-like Peptide-1 Analogues

Volume: 19 Issue: 2

Author(s): Wei Chen, Yinghong Zhou, Huibin Zhang, Hai Qian, Wenlong Huang, Baowei Yang, Jing Han, Jingpei Zhou, Yushi Chi and Shuaijian Ni

Affiliation:

Keywords: Site specific midification, plasma glucose, type 2 diatetes, combination therapy, Vildagliptin, proglucagon, analogue, His7-glucitol Glucagon-like peptide-1, DPP-IV, Xaa8-Glu21-Glu22-Glu23

Abstract: Glucagon-like peptide-1 (GLP-1) was once considered as an ideal anti-diabetic candidate for its important role in maintaining glucose homeostasis through the regulation of islet hormone secretion, as well as hepatic and gastric function. However, the major therapeutic obstacle for using native GLP-1 as a therapeutic agent is its very short half-life primarily due to their degradation by the enzyme dipeptidyl peptidase IV (DPP-IV). In this study, GLP-1 analogues with modifications in amino acid site 8, 22 and 23 were synthesized using solid phase peptide synthesis. Resistance of these analogues to DPP-IV cleavage was investigated in vitro by incubation of the peptides with DPP-IV or human plasma. Glucoregulating efficacy of the analogues was evaluated in normal Kunming mice using intraperitoneal glucose tolerance model. Glucose lowering effect of combination therapy (analogue plus Vildagliptin) has also been studied. In vitro studies showed that the modified analogues were much more stable than native GLP-1 (nearly 100% of the peptide keep intact after 4 h incubation). In vivo biological activity evaluation revealed that His8-EEE (the most potent GLP-1 analogues in this study) exhibited significantly improved glycemic control potency (approximately 4.1-fold over saline and 2.5-fold over GLP-1) and longer time of active duration (at least 5 h). Combination therapy also showed the trend of its superiority over mono-therapy. Modified analogues showed increased potency and biological half-time compared with the native GLP-1, which may help to understand the structure-activity relationship of GLP-1 analogues.

Cite this article as:

Chen Wei, Zhou Yinghong, Zhang Huibin, Qian Hai, Huang Wenlong, Yang Baowei, Han Jing, Zhou Jingpei, Chi Yushi and Ni Shuaijian, Stability and Bioactivity Studies on Dipeptidyl Peptidase IV Resistant Glucogan-like Peptide-1 Analogues, Protein & Peptide Letters 2012; 19 (2) . https://dx.doi.org/10.2174/092986612799080194

DOI https://dx.doi.org/10.2174/092986612799080194	Print ISSN 0929-8665
Publisher Name Bentham Science Publisher	Online ISSN 1875-5305