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J. Biol. Chem., Vol. 279, Issue 6, 3998-4006, February 6, 2004

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[Ser²]- and [Ser(P)²]Incretin Analogs

COMPARISON OF DIPEPTIDYL PEPTIDASE IV RESISTANCE AND BIOLOGICAL ACTIVITIES IN VITRO AND IN VIVO^*

Simon A. Hinke, Susanne Manhart¶, Kerstin Kühn-Wache¶, Cuilan Nian, Hans-Ulrich Demuth¶, Raymond A. Pederson, and Christopher H. S. McIntosh||

From the Department of Physiology, University of British Columbia, Vancouver, British Columbia V6T 1Z3, Canada and ^¶Probiodrug AG, Biocenter, Halle (Saale) D-06120, Germany

Glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP; also known as gastric inhibitory polypeptide) are incretin hormones that reduce postprandial glycemic excursions via enhancing insulin release but are rapidly inactivated by enzymatic N-terminal truncation. As such, efforts have been made to improve their plasma stability by synthetic modification or by inhibition of the responsible protease, dipeptidyl peptidase (DP) IV. Here we report a parallel comparison of synthetic GIP and GLP-1 with their Ser²- and Ser(P)²-substituted analogs, examining receptor binding and activation, metabolic stability, and biological effects in vivo. Both incretins and their Ser²-substituted analogs showed similar EC₅₀s (0.16–0.52 nM) and IC₅₀s (4.3–8.1 nM) at their respective cloned receptors. Although both phosphoserine 2-modified (Ser(PO₃H₂); Ser(P)) peptides were able to stimulate maximal cAMP production and fully displace receptor-bound tracer, they showed significantly right-shifted concentration-response curves and binding affinities. Ser²-substituted analogs were moderately resistant to DP IV cleavage, whereas [Ser(P)²]GIP and [Ser(P)²] GLP-1 showed complete resistance to purified DP IV. It was shown that the Ser(P) forms were dephosphorylated in serum and thus in vivo act as precursor forms of Ser²-substituted analogs. When injected subcutaneously into conscious Wistar rats, all peptides reduced glycemic excursions (rank potency: [Ser(P)²]incretins [Ser²] incretins > native hormones). Insulin determinations indicated that the reductions in postprandial glycemia were at least in part insulin-mediated. Thus it has been shown that despite having low in vitro bioactivity using receptor-transfected cells, in vivo potency of [Ser(P)²] incretins was comparable with or greater than that of native or [Ser²]peptides. Hence, Ser(P)²-modified incretins present as novel glucose-lowering agents.

Received for publication, October 14, 2003

^* This work was supported by Canadian Institutes of Health Research Grant 590007 and Department of Science and Technology of Sachsen Anhalt Grant 9704/00116. 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.

Recipient of a Canadian Institutes of Health Research predoctoral fellowship. Present address: Diabetes Research Center, Vrije Universiteit Brussel, Brussels B-1090, Belgium.

^|| To whom correspondence should be addressed: Dept. of Physiology, Faculty of Medicine, University of British Columbia, 2146 Health Sciences Mall, Vancouver, British Columbia V6T 1Z3, Canada. Tel.: 604-822-3088; Fax: 604-822-6048; E-mail: mcintoch{at}interchange.ubc.ca.

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