Protein engineering strategies for sustained glucagon-like peptide-1 receptor-dependent control of glucose homeostasis.

Diabetes
Kristen M PichaKaryn T O'Neil

Abstract

We have developed a novel platform for display and delivery of bioactive peptides that links the biological properties of the peptide to the pharmacokinetic properties of an antibody. Peptides engineered in the MIMETIBODY platform have improved biochemical and biophysical properties that are quite distinct from those of Fc-fusion proteins. CNTO736 is a glucagon-like peptide 1 (GLP-1) receptor agonist engineered in our MIMETIBODY platform. It retains many activities of native GLP-1 yet has a significantly enhanced pharmacokinetic profile. Our goal was to develop a long-acting GLP-1 receptor agonist with sustained efficacy. In vitro and in vivo activity of CNTO736 was evaluated using a variety of rodent cell lines and diabetic animal models. Acute pharmacodynamic studies in diabetic rodents demonstrate that CNTO736 reduces fasting and postprandial glucose, decreases gastric emptying, and inhibits food intake in a GLP-1 receptor-specific manner. Reduction of food intake following CNTO736 dosing is coincident with detection of the molecule in the circumventricular organs of the brain and activation of c-fos in regions protected by the blood-brain barrier. Diabetic rodents dosed chronically with CNTO736 have lower fasting and postpr...Continue Reading

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Citations

Sep 22, 2010·PloS One·Qinghua WangGerald J Prud'homme
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Jun 9, 2020·Bioconjugate Chemistry·Caroline TsaoShaoyi Jiang

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Methods Mentioned

BETA
lipidation
transfection
density gradient purification
enzyme-linked immunosorbent assay
ELISA
X-ray

Software Mentioned

MIMETIBODY

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