Consequences of Isostructural Main‐Chain Modifications for the Design of Antimicrobial Foldamers: Helical Mimics of Host‐Defense Peptides Based on a Heterogeneous Amide/Urea Backbone

Claudon, Paul; Violette, Aude; Lamour, Karen; Décossas, Marion; Fournel, Sylvie; Heurtault, Béatrice; Godet, Julien; Mély, Yves; Jamart‐Grégoire, Brigitte; Averlant‐Petit, Marie‐Christine; Briand, Jean‐Paul; Duportail, Guy; Monteil, H.; Guichard, Gilles

doi:10.1002/ange.200905591

Cited by 50 publications

(61 citation statements)

References 22 publications

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“…37 The quest to overcome these challenges posed by innate HDPs has fueled the search for biomimetic oligomers over the past two decades. These oligomeric peptidomimetics such as β-peptides, 6,38–40 peptoids, 10,31,41–47 arylamide oligomers, 48 β-turn mimetics, 49,50 and others 12 have been able to proffer solutions to the problems mentioned above because of their unnatural backbone. Inspired by these findings, we have designed and investigated a few types of antimicrobial AApeptides.…”

Section: Function Of Aapeptidesmentioning

confidence: 99%

“…γ-AA7 and γ-AA8 (Figure 9), with the same charge distribution and hydrophobicity, were the most potent antimicrobial sulfono-γ-AApeptides in the library (Table 2). 12,45,73,74 Small-angle X-ray scattering (SAXS) showed that γ-AA8 is less helical than γ-AA7 , suggesting N-terminal acetylation has significant effects on folding. Interestingly, γ-AA8 showed antimicrobial activity that was better than that of γ-AA7 and is less hemolytic and cytotoxic to mammalian cells than γ-AA7 is.…”

Section: Function Of Aapeptidesmentioning

confidence: 99%

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Structure and Function of AApeptides

Bolarinwa

Nimmagadda

et al. 2017

Biochemistry

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The intrinsic drawbacks encountered in bioactive peptides in chemical biology and biomedical sciences have diverted research efforts to the development of sequence-specific peptidomimetics that are capable of mimicking the structure and function of peptides and proteins. Modifications in the backbone and/or the side chain of peptides have been explored to develop biomimetic molecular probes or drug leads for biologically important targets. To expand the family of oligomeric peptidomimetics to facilitate their further application, we recently developed a new class of peptidomimetics, AApeptides based on a chiral peptide nucleic acid backbone. AApeptides are resistant to proteolytic degradation and amenable to enormous chemical diversification. Moreover, they could mimic the primary structure of peptides and also fold into discrete secondary structure such as helices and turn-like structures. Furthermore, they have started to show promise in applications in material and biomedical sciences. Herein, we highlight the structural design and some function of AApeptides and present our perspective on their future development.

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Section: Function Of Aapeptidesmentioning

confidence: 99%

Section: Function Of Aapeptidesmentioning

confidence: 99%

Structure and Function of AApeptides

Bolarinwa

Nimmagadda

et al. 2017

Biochemistry

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“…27 These structural features have also proven to be important in conferring antimicrobial activity on peptidomimetic oligomers 35−41 and polymers, 42−47 including β-peptide-based structures composed, either entirely or in part, of β-amino acid residues. 48,49 Owing to their folding principles, structural diversity, secondary structure stability, 50,51 and resistance to proteolysis, 52 β-peptides represent a promising class of compounds to elucidate mechanisms of AMP activity and to template development of new antifungal therapeutics.…”

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confidence: 99%

Hydrophobicity and Helicity Regulate the Antifungal Activity of 14-Helical β-Peptides

et al. 2014

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Candida albicans is one of the most prevalent fungal pathogens, causing both mucosal candidiasis and invasive candidemia. Antimicrobial peptides (AMPs), part of the human innate immune system, have been shown to exhibit antifungal activity but have not been effective as pharmaceuticals because of low activity and selectivity in physiologically relevant environments. Nevertheless, studies on α-peptide AMPs have revealed key features that can be designed into more stable structures, such as the 14-helix of β-peptide-based oligomers. Here, we report on the ways in which two of those features, hydrophobicity and helicity, govern the activity and selectivity of 14-helical β-peptides against C. albicans and human red blood cells. Our results reveal both antifungal activity and hemolysis to correlate to hydrophobicity, with intermediate levels of hydrophobicity leading to high antifungal activity and high selectivity toward C. albicans. Helical structure-forming propensity further influenced this window of selective antifungal activity, with more stable helical structures eliciting specificity for C. albicans over a broader range of hydrophobicity. Our findings also reveal cooperativity between hydrophobicity and helicity in regulating antifungal activity and specificity. The results of this study provide critical insight into the ways in which hydrophobicity and helicity govern the activity and specificity of AMPs and identify criteria that may be useful for the design of potent and selective antifungal agents.

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“…Please do not adjust margins 3 were measured with an Agilent Supernova diffractometer using an Agilent Eos CCD detector. The structures were solved with direct methods and refined using Fourier techniques.…”

Section: Please Do Not Adjust Marginsmentioning

confidence: 99%

“…1,2 Foldamers are generally considered as artificial models for molecular folding, 3 but they may also find use in enzyme-like functions, for example as biomimetic receptors 4 and catalysts 5,6,7 . The most common bond type in foldamers is the amide bond with directional and relatively stable hydrogen bonding properties.…”

Section: Introductionmentioning

confidence: 99%

Conformational properties and folding analysis of a series of seven oligoamide foldamers

et al. 2016

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33 crystal structures (11 unsolvated and 22 solvates) of a series of seven oligoamide foldamers were analysed. The crystal structures revealed that despite the structural and environmental differences the series of foldamers prefer only two general conformations, a protohelical @-conformation and a sigmoidal S-conformation. Both conformations also have preferred crystal packing motifs and solvate forming tendencies. Hydrogen bonding was found to be the most decisive factor in conformational preference, but steric properties, the type of the peripheral substituents, as well as solvent and aromatic interactions were also found to have an effect on the conformational details and crystal form.

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Consequences of Isostructural Main‐Chain Modifications for the Design of Antimicrobial Foldamers: Helical Mimics of Host‐Defense Peptides Based on a Heterogeneous Amide/Urea Backbone

Cited by 50 publications

References 22 publications

Structure and Function of AApeptides

Structure and Function of AApeptides

Hydrophobicity and Helicity Regulate the Antifungal Activity of 14-Helical β-Peptides

Conformational properties and folding analysis of a series of seven oligoamide foldamers

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