Macrocyclic Tetramers-Structural Investigation of Peptide-Peptoid Hybrids.

Anna Sonnefeld,Claudia Muhle-Goll,Thomas Gloge,Luisa Chiara Schlee,Stefan Bräse,Claudine Nicole Herlan,Julian Brückel,Martin Nieger

doi:10.3390/molecules26154548

Anna Sonnefeld, Claudia Muhle-Goll + Show 6 more

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https://doi.org/10.3390/molecules26154548

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Abstract

Outstanding affinity and specificity are the main characteristics of peptides, rendering them interesting compounds for basic and medicinal research. However, their biological applicability is limited due to fast proteolytic degradation. The use of mimetic peptoids overcomes this disadvantage, though they lack stereochemical information at the α-carbon. Hybrids composed of amino acids and peptoid monomers combine the unique properties of both parent classes. Rigidification of the backbone increases the affinity towards various targets. However, only little is known about the spatial structure of such constrained hybrids. The determination of the three-dimensional structure is a key step for the identification of new targets as well as the rational design of bioactive compounds. Herein, we report the synthesis and the structural elucidation of novel tetrameric macrocycles. Measurements were taken in solid and solution states with the help of X-ray scattering and NMR spectroscopy. The investigations made will help to find diverse applications for this new, promising compound class.

Highlights

Peptides, a structurally and functionally diverse class of macromolecules, are involved in all parts of life
Peptides come along with some drawbacks limiting their applicability as selective therapeutics: fast proteolytic degradation resulting in low bioavailability and improvable physicochemical properties [3,4]
Macrocycles made up of four monomer we aimed to synthesize a congener library of the cyclic tetrapeptide

Summary

Introduction

A structurally and functionally diverse class of macromolecules, are involved in all parts of life. Their unique properties render them highly promising compounds for biochemical and medicinal research [1,2]. Peptides come along with some drawbacks limiting their applicability as selective therapeutics: fast proteolytic degradation resulting in low bioavailability and improvable physicochemical properties [3,4]. Cyclization has been shown to increase proteolytic resistance and even the binding affinity and specificity of linear peptides [5,6]. Fixed arrangements of functional moieties arouse outstanding bioactivities, especially in small cyclic peptides [7,8,9,10,11,12]. Nowadays several cyclic tetrapeptides that modify eukaryotic gene expression [13,14,15,16,17,18,19,20], that interact with cellular receptors [11,21,22,23,24,25] or that display antimicrobial activity [12,26,27,28,29,30]

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