A GLP-1 receptor agonist conjugated to an albumin-binding domain for extended half-life
2014 (English)In: Biopolymers, ISSN 0006-3525, E-ISSN 1097-0282, Vol. 102, no 3, 252-259 p.Article in journal (Refereed) Published
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.
Place, publisher, year, edition, pages
2014. Vol. 102, no 3, 252-259 p.
glucagon-like peptide 1, albumin-binding domain, half-life extension, peptide conjugate, insulin release
Biochemistry and Molecular Biology
Research subject Biotechnology
IdentifiersURN: urn:nbn:se:kth:diva-141009DOI: 10.1002/bip.22474ISI: 000337513400004ScopusID: 2-s2.0-84922005237OAI: oai:DiVA.org:kth-141009DiVA: diva2:693804
Updated from Manuscript to Journal. QC 201407112014-02-052014-02-052014-07-11Bibliographically approved