Design of a long acting peptide functioning as both a glucagon-like peptide-1 receptor agonist and a glucagon receptor antagonist.
The closely related peptides glucagon-like peptide (GLP-1) and glucagon have opposing effects on blood glucose. GLP-1 induces glucose-dependent insulin secretion in the pancreas, whereas glucagon stimulates gluconeogenesis and glycogenolysis in the liver. The identification of a hybrid peptide acting as both a GLP-1 agonist and a glucagon antagonist would provide a novel approach for the treatment of type 2 diabetes. Toward this end a series of hybrid peptides made up of glucagon and either GLP-1 or exendin-4, a GLP-1 agonist, was engineered. Several peptides that bind to both the GLP-1 and glucagon receptors were identified. The presence of glucagon sequence at the N terminus removed the dipeptidylpeptidase IV cleavage site and increased plasma stability compared with GLP-1. Targeted mutations were incorporated into the optimal dual-receptor binding peptide to identify a peptide with the highly novel property of functioning as both a GLP-1 receptor agonist and a glucagon receptor antagonist. To overcome the short half-life of this mutant peptide in vivo, while retaining dual GLP-1 agonist and glucagon antagonist activities, site-specific attachment of long chained polyethylene glycol (PEGylation) was pursued. PEGylation at the C terminus retained the in vitro activities of the peptide while dramatically prolonging the duration of action in vivo. Thus, we have generated a novel dual-acting peptide with potential for development as a therapeutic for type 2 diabetes.
Pan
Clark Q
CQ
Department of Biotechnology, Bayer HealthCare, California 94701, USA.
Buxton
Joanne M
JM
Yung
Stephanie L
SL
Tom
Irene
I
Yang
Ling
L
Chen
Hongxing
H
MacDougall
Margit
M
Bell
Andrea
A
Claus
Thomas H
TH
Clairmont
Kevin B
KB
Whelan
James P
JP
D000595:Amino Acid Sequence; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy; D015195:Drug Design; D000067757:Glucagon-Like Peptide-1 Receptor; D006801:Humans; D008297:Male; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry*; D051381:Rats; D017207:Rats, Sprague-Dawley; D017208:Rats, Wistar; D018027:Receptors, Glucagon / Q000819:agonists / Q000037:antagonists & inhibitors*; D017386:Sequence Homology, Amino Acid
D001786:Blood Glucose; C000593833:GLP1R protein, human; C000593835:Glp1r protein, rat; D000067757:Glucagon-Like Peptide-1 Receptor; D010455:Peptides; D018027:Receptors, Glucagon