Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)-Selective Peptide-Peptoid Hybrids

Held C, Hübner H, Kling R, Nagel YA, Wennemers H, Gmeiner P (2013)

Publication Language: English

Publication Type: Journal article, Original article

Publication year: 2013

Journal

ChemMedChem Wiley

Original Authors: Held C., Hubner H., Kling R., Nagel Y.A., Wennemers H., Gmeiner P.

Publisher: Wiley-VCH Verlag

Book Volume: 8

Pages Range: 772-778

Journal Issue: 5

DOI: 10.1002/cmdc.201300054

Abstract

To investigate the binding mode and structure-activity relationships (SARs) of selective neurotensin receptor2 (NTS2) ligands, novel peptide-peptoid hybrids that simulate the function of the endogenous ligand were developed. Starting from our recently described NTS2 ligands of type 1, structural variants of type 2 and the metabolically stable analogues 3a,b were developed. Replacement of the proline unit by a collection of structural surrogates and evaluation of the respective molecular probes for NTS2 affinity and selectivity indicated similar SARs as described for NT(8-13) derivatives bound to the subtype NTS1. Peptide-peptoid hybrids 2d, 3a,b showed substantial NTS2 binding affinity (K=8.1-16nM) and 2400-8600-fold selectivity over NTS1. The thiazolidine derivative 3b showed metabolic stability over 32h in a serum degradation assay. In an inositol phosphate accumulation assay, the neurotensin mimetics 3a and 3b displayed an inhibition of constitutive activity exceeding 1.7-2.0times the activity of NT(8-13). The fluorinated derivative 3a could afford attractive opportunities to detect NTS2 by F magnetic resonance imaging. © 2013 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.

Authors with CRIS profile

Cornelia Held Lehrstuhl für Pharmazeutische Chemie Harald Hübner Lehrstuhl für Pharmazeutische Chemie Ralf Kling Lehrstuhl für Pharmazeutische Chemie Peter Gmeiner Lehrstuhl für Pharmazeutische Chemie

Additional Organisation(s)

Emil-Fischer-Zentrum (Emil Fischer Center)

Involved external institutions

Eidgenössische Technische Hochschule Zürich (ETHZ) / Swiss Federal Institute of Technology in Zurich CH Switzerland (CH)

How to cite

APA:

Held, C., Hübner, H., Kling, R., Nagel, Y.A., Wennemers, H., & Gmeiner, P. (2013). Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)-Selective Peptide-Peptoid Hybrids. ChemMedChem, 8(5), 772-778. https://dx.doi.org/10.1002/cmdc.201300054

MLA:

Held, Cornelia, et al. "Impact of the Proline Residue on Ligand Binding of Neurotensin Receptor 2 (NTS2)-Selective Peptide-Peptoid Hybrids." ChemMedChem 8.5 (2013): 772-778.

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