title: 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.
abstract: 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.
authors.affiliation: Alteogen, Inc., Bioventure Town, Daejeon 305-812, South Korea. hschung@hnu.kr
authors.forename: Hye-Shin
authors.initials: HS
authors.lastname: Chung
authors.forename: Ji-Yeon
authors.initials: JY
authors.lastname: Oh
authors.forename: Seung-Bum
authors.initials: SB
authors.lastname: Yoo
authors.forename: Sang Mee
authors.initials: SM
authors.lastname: Lee
authors.forename: Heung-Soo
authors.initials: HS
authors.lastname: Cho
mesh_terms: D020816:Amino Acid Motifs; D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000187:drug effects*; D018819:Dipeptidyl Peptidase 4; D052216:Glucagon-Like Peptide 1 / Q000096:biosynthesis* / Q000494:pharmacology; D006207:Half-Life; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics / Q000494:pharmacology*; D007141:Immunoglobulin Fc Fragments / Q000096:biosynthesis* / Q000494:pharmacology; D007074:Immunoglobulin G / Q000096:biosynthesis* / Q000494:pharmacology; D051379:Mice; D016688:Mice, Inbred NOD; D008969:Molecular Sequence Data; D051381:Rats; D017207:Rats, Sprague-Dawley; D011993:Recombinant Fusion Proteins / Q000096:biosynthesis* / Q000493:pharmacokinetics / Q000494:pharmacology; D020539:Sequence Analysis, Protein
chemical_list: D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007141:Immunoglobulin Fc Fragments; D007074:Immunoglobulin G; D011993:Recombinant Fusion Proteins; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4