Disulfide bond prolongs the half-life of therapeutic peptide-GLP-1.

The multiple physiological characterization of glucagon-like peptide-1 (GLP-1) makes it a promising drug candidate for the therapy of type 2 diabetes. However, the half-life of GLP-1 is short in vivo due to rapid degradation by dipeptidyl peptidase-IV (DPP-IV) and renal clearance. This indicates that the stabilization of GLP-1 is critical for its utility in drug development. In this study, we developed a cluster of GLP-1 homodimeric analogs, which fused the mutated GLP-1 monomer by an intra-disulfide bridge. The stabilities of the GLP-1 homodimeric analogs were investigated and the physiological functions of the analogs were compared with those of wild-type GLP-1 in rats and human serum. Single dose glucose tolerance test was performed to investigate the administration frequency which satisfied the efficient glucose regulatory in rats. Multiple dose glucose tolerance tests were employed also to study the long-acting anti-diabetic activity of GLP-1 homodimeric analog. The results indicated that the GLP-1 homodimeric analog (hdGLP1G10C) remarkably raised the biological half-life of GLP-1; also HDGLP1G10C showed better glucose tolerance and higher HbA(1c) reduction than GLP-1 in rodents. Based upon the results in this study, it was suggested that hdGLP1G10C prolonged the stability of GLP-1 and retained the biological activity of GLP-1. The improved physiological characterization of hdGLP1G10C makes it as possible potent anti-diabetic drug in the treatment of type 2 diabetes mellitus.