title: A GLP-1 receptor agonist conjugated to an albumin-binding domain for extended half-life.
abstract: Glucagon-like peptide 1 (GLP-1) and related peptide agonists have been extensively investigated for glycaemic control in Type 2 diabetes, and may also have therapeutic applications for other diseases. Due to the short half-life (t1/2  < 2 min) of the endogenous peptide, caused by proteolytic degradation and renal clearance, different strategies for half-life extension and sustained release have been explored. In the present study, conjugates between a GLP-1 analogue and a 5 kDa albumin-binding domain (ABD) derived from streptococcal protein G have been chemically synthesized and evaluated. ABD binds with high affinity to human serum albumin, which is highly abundant in plasma and functions as a drug carrier in the circulation. Three different GLP-1-ABD conjugates, with the two peptides connected by linkers of two, four, and six PEG units, respectively, were synthesized and tested in mouse pancreatic islets at high (11 mM) and low (3 mM) glucose concentration. Insulin release upon stimulation was shown to be glucose-dependent, showing no significant difference between the three different GLP-1-ABD conjugates and unconjugated GLP-1 analogue. The biological activity, in combination with the high affinity binding to albumin, make the GLP-1-ABD conjugates promising GLP-1 receptor agonists expected to show extended in vivo half-life.
authors.affiliation: Division of Protein Technology, School of Biotechnology, KTH Royal Institute of Technology, AlbaNova University Center, SE 106 91, Stockholm, Sweden.
authors.forename: Joel
authors.initials: J
authors.lastname: Lindgren
authors.forename: Essam
authors.initials: E
authors.lastname: Refai
authors.forename: Sergei V
authors.initials: SV
authors.lastname: Zaitsev
authors.forename: Lars
authors.initials: L
authors.lastname: Abrahmsén
authors.forename: Per-Olof
authors.initials: PO
authors.lastname: Berggren
authors.forename: Amelie Eriksson
authors.initials: AE
authors.lastname: Karlström
mesh_terms: D000818:Animals; D015374:Biosensing Techniques; D002851:Chromatography, High Pressure Liquid; D056148:Chromatography, Reverse-Phase; D000067757:Glucagon-Like Peptide-1 Receptor / Q000737:chemistry*; D006207:Half-Life; D006801:Humans; D007328:Insulin / Q000378:metabolism; D000078790:Insulin Secretion; D007515:Islets of Langerhans; D008820:Mice, Obese; D010455:Peptides / Q000138:chemical synthesis / Q000737:chemistry; D017434:Protein Structure, Tertiary; D051381:Rats; D012709:Serum Albumin / Q000737:chemistry*; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
chemical_list: D000067757:Glucagon-Like Peptide-1 Receptor; D007328:Insulin; D010455:Peptides; D012709:Serum Albumin; D000097789:Glucagon-Like Peptide-1 Receptor Agonists
keywords: albumin-binding domain; glucagon-like peptide 1; half-life extension; insulin release; peptide conjugate