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

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

doi:10.1021/ja507168t

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

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Author(s): 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 ^† ^,

Publication date (Electronic): 05 September 2014

Journal: Journal of the American Chemical Society

Publisher: American Chemical Society

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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.

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Most cited references 25

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Foldamers as versatile frameworks for the design and evolution of function.

William DeGrado, Sungwook Choi, Scott Shandler … (2007)

Foldamers are sequence-specific oligomers akin to peptides, proteins and oligonucleotides that fold into well-defined three-dimensional structures. They offer the chemical biologist a broad pallet of building blocks for the construction of molecules that test and extend our understanding of protein folding and function. Foldamers also provide templates for presenting complex arrays of functional groups in virtually unlimited geometrical patterns, thereby presenting attractive opportunities for the design of molecules that bind in a sequence- and structure-specific manner to oligosaccharides, nucleic acids, membranes and proteins. We summarize recent advances and highlight the future applications and challenges of this rapidly expanding field.

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Glucagon-like peptide-1-(7-36)amide is transformed to glucagon-like peptide-1-(9-36)amide by dipeptidyl peptidase IV in the capillaries supplying the L cells of the porcine intestine.

L. Hansen, C F Deacon, C Orskov … (1999)

The insulinotropic hormone glucagon-like peptide-1 (GLP-1) is stored in the intestinal L cell in an active form, GLP-1-(7-36)amide, but more than half of the endogenous peptide circulates in an inactive, N-terminally truncated form, GLP-1-(9-36)amide. This study examined the GLP-1 newly secreted from the porcine ileum, in vitro (isolated perfused preparation) and in vivo (anesthetized pig), to determine where this conversion occurs. Although the GLP-1 extractable from the porcine ileum is predominantly the intact peptide (94.6+/-1.7%), a large proportion of the GLP-1 that is secreted has already been degraded to the truncated form both in vitro (53.8+/-0.9% intact) and in vivo (32.9+/-10.8% intact). In the presence of a specific dipeptidyl peptidase IV (DPP IV) inhibitor (valine-pyrrolidide), the proportion of intact GLP-1 released from the perfused ileum was increased under both basal (99% intact; P < 0.05) and stimulated (86-101% intact; P < 0.05) conditions. Immunohistochemical and histochemical studies revealed specific DPP IV staining in the brush border epithelium as well as in the capillary endothelium. Double staining showed juxtapositioning of DPP IV-positive capillaries and GLP-1-containing L cells. From these results, we suggest that GLP-1 is degraded as it enters the DPP IV containing blood vessels draining the intestinal mucosa.