A Potent α/β-Peptide Analogue of GLP-1 with Prolonged Action in Vivo

Lisa M. Johnson; Stacey Barrick; Marlies V. Hager; Amanda McFedries; Edwin A. Homan; Mary E. Rabaglia; Mark P. Keller; Alan D. Attie; Alan Saghatelian; Alessandro Bisello; Samuel H. Gellman

doi:10.1021/ja507168t

A Potent α/β-Peptide Analogue of GLP-1 with Prolonged Action in Vivo

Lisa M. Johnson, Stacey Barrick, Marlies V. Hager, Amanda McFedries, Edwin A. Homan, Mary E. Rabaglia, Mark P. Keller, Alan D. Attie, Alan Saghatelian, Alessandro Bisello, Samuel H. Gellman

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Abstract

Glucagon-like peptide-1 (GLP-1) is a natural agonist for GLP-1R, a G protein-coupled receptor (GPCR) on the surface of pancreatic β cells. GLP-1R agoinsts are attractive for treatment of type 2 diabetes, but GLP-1 itself is rapidly degraded by peptidases in vivo. We describe a design strategy for retaining GLP-1-like activity while engendering prolonged activity in vivo, based on strategic replacement of native α residues with conformationally constrained β-amino acid residues. This backbone-modification approach may be useful for developing stabilized analogues of other peptide hormones.

Original language	English (US)
Pages (from-to)	12848-12851
Number of pages	4
Journal	Journal of the American Chemical Society
Volume	136
Issue number	37
DOIs	https://doi.org/10.1021/ja507168t
State	Published - Sep 5 2015
Externally published	Yes

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© 2014 American Chemical Society.

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AU - Johnson, Lisa M.

AU - Barrick, Stacey

AU - Hager, Marlies V.

AU - McFedries, Amanda

AU - Homan, Edwin A.

AU - Rabaglia, Mary E.

AU - Keller, Mark P.

AU - Attie, Alan D.

AU - Saghatelian, Alan

AU - Bisello, Alessandro

AU - Gellman, Samuel H.

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A Potent α/β-Peptide Analogue of GLP-1 with Prolonged Action in Vivo

Abstract

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