The N-terminal alanine-extended GLP-1/IgG-Fc fusion protein confers resistance to DPP-IV and reduces serum glucose level in db/db mice

• Published in: Regulatory peptides 2011-10, Vol.170 (1), p.1-3
• Main Authors: Chung, Hye-Shin, Oh, Ji-Yeon, Yoo, Seung-Bum, Lee, Sang Mee, Cho, Heung-Soo
• Format: Article
• Language: English
• Subjects: Amino Acid Motifs; Amino Acid Sequence; Animals; Biological and medical sciences; Blood Glucose - drug effects; Diabetes. Impaired glucose tolerance; Dipeptidyl Peptidase 4; Dipeptidyl peptidase IV (DPPIV); Endocrine pancreas. Apud cells (diseases); Endocrinopathies; Etiopathogenesis. Screening. Investigations. Target tissue resistance; Fundamental and applied biological sciences. Psychology; Glucagon-like peptide 1 (GLP-1); Glucagon-Like Peptide 1 - biosynthesis; Glucagon-Like Peptide 1 - pharmacology; Half-Life; Hypoglycemic Agents - pharmacokinetics; Hypoglycemic Agents - pharmacology; IgG-Fc fusion; Immunoglobulin Fc Fragments - biosynthesis; Immunoglobulin Fc Fragments - pharmacology; Immunoglobulin G - biosynthesis; Immunoglobulin G - pharmacology; Medical sciences; Mice; Mice, Inbred NOD; Molecular Sequence Data; Rats; Rats, Sprague-Dawley; Recombinant Fusion Proteins - biosynthesis; Recombinant Fusion Proteins - pharmacokinetics; Recombinant Fusion Proteins - pharmacology; Sequence Analysis, Protein; Type 2 diabetes; Vertebrates: endocrinology
• ISSN: 0167-0115; 1873-1686
• DOI: 10.1016/j.regpep.2011.05.002

The aim of this study was to develop novel long-acting glucagon-like peptide 1 (GLP-1) analogs resistant to dipeptidyl peptidase-IV (DPP-IV). We constructed three fusion proteins comprising GLP-1 and the human immunoglobulin gamma heavy chain (IgG-Fc); wild-type GLP-1 and IgG-Fc (GLP-1/IgG-Fc) and two N-terminal-extended fusion proteins in which an additional Ala (A) or Gly (G) was located on the N-terminus of GLP-1 (A-GLP-1/IgG-Fc or G-GLP-1/IgG-Fc). The fusion proteins expressed in CHO-K1 cells were secreted into medium and purified by Protein A affinity chromatography. Here, we show that the Ala or Gly-extended GLP-1/IgG-Fc fusion protein is resistant to DPP-IV and has increased half-life in vivo. To our surprise, the A-GLP-1/IgG-Fc fusion protein was more effective than wildtype GLP-1/IgG-Fc fusion protein in reducing blood glucose levels in db/db mice. Our findings suggest that the A-GLP-1/IgG-Fc fusion protein could be a potential long-acting GLP-1 receptor agonist for the treatment of insulin-resistant type 2 diabetes.