Synthesis and Bioactivity Evaluation of Dipeptidyl Peptidase IV Resistant Glucagon-like Peptide-1 Analogues

Author(s): Jinpei Zhou , Shuaijian Ni , Huibin Zhang , Hai Qian , Yushi Chi , Wenlong Huang , Lu Yu , Xiaowen Hu , Wei Chen .

Journal Name: Protein & Peptide Letters

Volume 17 , Issue 10 , 2010

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Abstract:

Glucagon-like peptide -1 (GLP-1) is an incretin hormone displaying glucose-dependent stimulation of insulin secretion and trophic effects on the pancreatic β-cells. However, GLP-1 is rapidly degraded to GLP-1(9-36) by dipeptidyl peptidase-IV (DPP-IV), which removes the N-terminal dipeptide His7-Ala8. The rapid inactivation of GLP-1 in the blood circulation limits its clinical application. Hence, we replaced the enzymatic hydrolyzation position Ala8 with other natural amino acids. The GLP-1 analogues were synthesized rapidly and efficiently under microwave irradiation, using Fmoc/tBu orthogonal protection strategy. Studies on blood-glucose-lowering effect of GLP-1 analogues in vivo were undertaken using 10-week-old male Kunming mice. The metabolic stability was tested by incubation with dipeptidyl peptidase-IV (DPP-IV). Generally, Xaa8-GLP-1 analogues exhibit resistance to DPP-IV degradation in vitro and stronger hypoglycemic effect than GLP-1. This may help to understand the structure-activity relationship of GLP-1 analogues.

Keywords: Glucagon-like peptide-1, microwave assisted synthesis, solid phase peptide synthesis, hypoglycemic

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Article Details

VOLUME: 17
ISSUE: 10
Year: 2010
Page: [1290 - 1295]
Pages: 6
DOI: 10.2174/092986610792231546
Price: $58

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