Volume 23, Issue 15 p. 3699-3707
Full Paper

α-Aminoxy Peptoids: A Unique Peptoid Backbone with a Preference for cis-Amide Bonds

Viktoria Krieger

Viktoria Krieger

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Dr. Emanuele Ciglia

Dr. Emanuele Ciglia

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Roland Thoma

Roland Thoma

Institute of Inorganic and Structural Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Dr. Vera Vasylyeva

Dr. Vera Vasylyeva

Institute of Inorganic and Structural Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Benedikt Frieg

Benedikt Frieg

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Dr. Nader de Sousa Amadeu

Dr. Nader de Sousa Amadeu

Institute of Inorganic and Structural Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Prof. Dr. Thomas Kurz

Prof. Dr. Thomas Kurz

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Prof. Dr. Christoph Janiak

Prof. Dr. Christoph Janiak

Institute of Inorganic and Structural Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Prof. Dr. Holger Gohlke

Prof. Dr. Holger Gohlke

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

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Prof. Dr. Finn K. Hansen

Corresponding Author

Prof. Dr. Finn K. Hansen

Institute of Pharmaceutical and Medicinal Chemistry, Heinrich-Heine-Universität Düsseldorf, Universitätsstrasse 1, 40225 Düsseldorf, Germany

Pharmaceutical/Medicinal Chemistry, Institute of Pharmacy, Leipzig University, Brüderstrasse 34, 04103 Leipzig, Germany

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First published: 16 January 2017
Citations: 9

Graphical Abstract

The first thorough analysis of the folding propensities of α-aminoxy peptoids has been performed. This novel foldamer class shows a unique preference for cis-amide bonds. The conformational analysis based on MD simulations revealed that α-aminoxy peptoids can adopt helical conformations that can mimic the spatial arrangement of peptide side chains in a canonical α-helix (see figure).

Abstract

α-Peptoids, or N-substituted glycine oligomers, are an important class of peptidomimetic foldamers with proteolytic stability. Nevertheless, the presence of cis/trans-amide bond conformers, which contribute to the high flexibility of α-peptoids, is considered as a major drawback. A modified peptoid backbone with an improved control of the amide bond geometry could therefore help to overcome this limitation. Herein, we have performed the first thorough analysis of the folding propensities of α-aminoxy peptoids (or N-substituted 2-aminoxyacetic acid oligomers). To this end, the amide bond geometry and the conformational properties of a series of model α-aminoxy peptoids were investigated by using 1D and 2D NMR experiments, X-ray crystallography, natural bond orbital (NBO) analysis, circular dichroism (CD) spectroscopy, and molecular dynamics (MD) simulations revealing a unique preference for cis-amide bonds even in the absence of cis-directing side chains. The conformational analysis based on the MD simulations revealed that α-aminoxy peptoids can adopt helical conformations that can mimic the spatial arrangement of peptide side chains in a canonical α-helix. Given their ease of synthesis and conformational properties, α-aminoxy peptoids represent a new member of the peptoid family capable of controlling the amide isomerism while maintaining the potential for side-chain diversity.