Structural Characterization of a Novel GLP-1 Analog Taspoglutide by NMR Spectroscopy

摘要

Glucagon-like peptide-1 (GLP-1) is a glucose-dependent insulinotropic agent. It stimulates insulin secretion and inhibits glucagon release in a strictly glucose-dependent manner. GLP-1 also promotes insulin gene expression and biosynthesis, induces pancreatic β-cell proliferation, slows gastric emptying and suppresses appetite. These unique properties make GLP-1 a potentially important treatment of type 2 diabetes. However, native GLP-1 is rapidly degraded by proteases in vivo and the short circulating half-life greatly hampers its clinical utility [1]. After the extensive investigation on the GLP-1 structural elements that influence the potency and enzymatic stability, a novel human GLP-1 analog [Aib~(8.35)]hGLP-l(7-36)-NH2 (Taspoglutide) was designed [1-3]. The introduction of a-aminoisobutyric acid (Aib) at positions 8 and 35 protects both N- and C- terminal peptide bonds from enzymatic cleavage and results in increased circulating half-life [3]. In addition, the Aib8'35 mutations enhance a-helical content, especially in the C-terminal region. The combination of the high enzymatic stability and stronger C-terminal a-helix makes the analog highly efficacious in stimulating the insulin release in vivo. In this particular study, we analyzed the impact of Aib~(8.35) substitutions on the secondary structure of the peptide using NMR spectroscopy.