Transferrin fusion technology: a novel approach to prolonging biological half-life of insulinotropic peptides.
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.
Kim
Byung-Joon
BJ
National Institute on Aging, National Institutes of Health, Baltimore, Maryland 21224, USA.
Zhou
Jie
J
Martin
Bronwen
B
Carlson
Olga D
OD
Maudsley
Stuart
S
Greig
Nigel H
NH
Mattson
Mark P
MP
Ladenheim
Ellen E
EE
Wustner
Jay
J
Turner
Andrew
A
Sadeghi
Homayoun
H
Egan
Josephine M
JM
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*
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