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J. Biol. Chem., Vol. 281, Issue 18, 12506-12515, May 5, 2006

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Design of a Long Acting Peptide Functioning as Both a Glucagon-like Peptide-1 Receptor Agonist and a Glucagon Receptor Antagonist^*

Clark Q. Pan, Joanne M. Buxton, Stephanie L. Yung, Irene Tom, Ling Yang, Hongxing Chen, Margit MacDougall, Andrea Bell, Thomas H. Claus, Kevin B. Clairmont, and James P. Whelan¹

From the Department of Biotechnology, Bayer HealthCare, California 94701 and the Department of Metabolic Disease Research, Bayer HealthCare, Pharmaceuticals, West Haven, Connecticut 06516

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.

Received for publication, January 5, 2006 , and in revised form, February 15, 2006.

^* The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

¹ To whom correspondence should be addressed: Bayer HealthCare, Pharmaceuticals, Dept. of Metabolic Disease Research, 400 Morgan Lane, West Haven, CT 06516. Tel.: 203-812-2131; Fax: 203-812-2686; E-mail: james.whelan.b{at}bayer.com.

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				T. H Claus, C. Q Pan, J. M Buxton, L. Yang, J. C Reynolds, N. Barucci, M. Burns, A. A Ortiz, S. Roczniak, J. N Livingston, et al. Dual-acting peptide with prolonged glucagon-like peptide-1 receptor agonist and glucagon receptor antagonist activity for the treatment of type 2 diabetes J. Endocrinol., February 1, 2007; 192(2): 371 - 380. [Abstract] [Full Text] [PDF]

				C. Q. Pan, F. Li, I. Tom, W. Wang, M. Dumas, W. Froland, S. L. Yung, Y. Li, S. Roczniak, T. H. Claus, et al. Engineering Novel VPAC2-Selective Agonists with Improved Stability and Glucose-Lowering Activity in Vivo J. Pharmacol. Exp. Ther., February 1, 2007; 320(2): 900 - 906. [Abstract] [Full Text] [PDF]