title: Transferrin fusion technology: a novel approach to prolonging biological half-life of insulinotropic peptides.
abstract: Fusion proteins made up of glucagon-like peptide 1 (GLP-1) and exendin-4 (EX-4) fused to a nonglycosylated form of human transferrin (GLP-1-Tf or EX-4-Tf) were produced and characterized. GLP-1-Tf activated the GLP-1 receptor, was resistant to inactivation by peptidases, and had a half-life of approximately 2 days, compared with 1 to 2 min for native GLP-1. GLP-1-Tf retained the acute, glucose-dependent insulin-secretory properties of native GLP-1 in diabetic animals and had a profound effect on proliferation of pancreatic beta-cells. In addition, Tf and the fusion proteins did not cross the blood-brain-barrier but still reduced food intake after peripheral administration. EX-4-Tf proved to be as effective as EX-4 but had longer lived effects on blood glucose and food intake. This novel transferrin fusion technology could improve the pharmacology of various peptides.
authors.affiliation: National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
authors.forename: Byung-Joon
authors.initials: BJ
authors.lastname: Kim
authors.forename: Jie
authors.initials: J
authors.lastname: Zhou
authors.forename: Bronwen
authors.initials: B
authors.lastname: Martin
authors.forename: Olga D
authors.initials: OD
authors.lastname: Carlson
authors.forename: Stuart
authors.initials: S
authors.lastname: Maudsley
authors.forename: Nigel H
authors.initials: NH
authors.lastname: Greig
authors.forename: Mark P
authors.initials: MP
authors.lastname: Mattson
authors.forename: Ellen E
authors.initials: EE
authors.lastname: Ladenheim
authors.forename: Jay
authors.initials: J
authors.lastname: Wustner
authors.forename: Andrew
authors.initials: A
authors.lastname: Turner
authors.forename: Homayoun
authors.initials: H
authors.lastname: Sadeghi
authors.forename: Josephine M
authors.initials: JM
authors.lastname: Egan
mesh_terms: D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D016466:CHO Cells; D049109:Cell Proliferation / Q000187:drug effects; D006224:Cricetinae; D003412:Cricetulus; D003920:Diabetes Mellitus / Q000188:drug therapy / Q000235:genetics / Q000378:metabolism; D018819:Dipeptidyl Peptidase 4 / Q000378:metabolism; D004435:Eating / Q000187:drug effects; D004797:Enzyme-Linked Immunosorbent Assay; D016762:Genes, fos / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000235:genetics; D000067757:Glucagon-Like Peptide-1 Receptor; D006207:Half-Life; D006801:Humans; D007004:Hypoglycemic Agents / Q000493:pharmacokinetics*; D066298:In Vitro Techniques; D007328:Insulin / Q000378:metabolism*; D050417:Insulin-Secreting Cells / Q000187:drug effects; D007515:Islets of Langerhans / Q000187:drug effects / Q000378:metabolism; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D015202:Protein Engineering; D051381:Rats; D017207:Rats, Sprague-Dawley; D018027:Receptors, Glucagon / Q000819:agonists; D011993:Recombinant Fusion Proteins; D012441:Saccharomyces cerevisiae / Q000378:metabolism; D014168:Transferrin / Q000235:genetics*
chemical_list: D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593834:Glp1r protein, mouse; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D007004:Hypoglycemic Agents; D007328:Insulin; D018027:Receptors, Glucagon; D011993:Recombinant Fusion Proteins; D014168:Transferrin; D052216:Glucagon-Like Peptide 1; D018819:Dipeptidyl Peptidase 4