Urea based foldamers

Yoo, Sung Hyun; Li, Bo; Dolain, Christel; Pasco, Morgane; Guichard, Gilles

doi:10.1016/bs.mie.2021.04.019

Cited by 13 publications

(14 citation statements)

References 76 publications

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“…Urea-type helical foldamers are classified as a type of γ-peptide in which a methylamino motif is inserted into α-amino acids and have been used in drug discovery research [116,117]. In 1995, a solid-phase synthetic method was reported by Burgess et al [118,119].…”

Section: Urea-type Foldamersmentioning

confidence: 99%

Helical Foldamers and Stapled Peptides as New Modalities in Drug Discovery: Modulators of Protein-Protein Interactions

et al. 2022

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A “foldamer” is an artificial oligomeric molecule with a regular secondary or tertiary structure consisting of various building blocks. A “stapled peptide” is a peptide with stabilized secondary structures, in particular, helical structures by intramolecular covalent side-chain cross-linking. Helical foldamers and stapled peptides are potential drug candidates that can target protein-protein interactions because they enable multipoint molecular recognition, which is difficult to achieve with low-molecular-weight compounds. This mini-review describes a variety of peptide-based foldamers and stapled peptides with a view to their applications in drug discovery, including our recent progress.

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Section: Urea-type Foldamersmentioning

confidence: 99%

Helical Foldamers and Stapled Peptides as New Modalities in Drug Discovery: Modulators of Protein-Protein Interactions

et al. 2022

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“…This general design was further extended to arylurea foldamers [ 18 ]. Compared to other peptidomimetic foldamers, aliphatic urea-based foldamers (of general formula [-CH(R)-CH 2 -NH-CO-NH] n ) [ 19 ] ( Figure 1 ) possess several features that make them promising candidates for biological applications as therapeutics: (i) short chain N,N′-linked oligoureas adopt a helical conformation in aqueous solution (2.5-residues per turn) akin to the α-helix [ 20 ]; (ii) this conformational preference is largely independent of the primary sequence; (iii) synthetic accessibility allows the incorporation of all proteinogenic amino acid side chains; and (iv) the oligourea backbone is resistant towards enzymatic degradation [ 21 ].…”

Section: Introductionmentioning

confidence: 99%

Design of Oligourea-Based Foldamers with Antibacterial and Antifungal Activities

et al. 2022

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There is an urgent need to develop new therapeutic strategies to fight the emergence of multidrug resistant bacteria. Many antimicrobial peptides (AMPs) have been identified and characterized, but clinical translation has been limited partly due to their structural instability and degradability in physiological environments. The use of unnatural backbones leading to foldamers can generate peptidomimetics with improved properties and conformational stability. We recently reported the successful design of urea-based eukaryotic cell-penetrating foldamers (CPFs). Since cell-penetrating peptides and AMPs generally share many common features, we prepared new sequences derived from CPFs by varying the distribution of histidine- and arginine-type residues at the surface of the oligourea helix, and evaluated their activity on both Gram-positive and Gram-negative bacteria as well as on fungi. In addition, we prepared and tested new amphiphilic block cofoldamers consisting of an oligourea and a peptide segment whereby polar and charged residues are located in the peptide segment and more hydrophobic residues in the oligourea segment. Several foldamer sequences were found to display potent antibacterial activities even in the presence of 50% serum. Importantly, we show that these urea-based foldamers also possess promising antifungal properties.

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“…Foldamers are unnatural oligomers that adopt stable, ordered and predictable conformations in solution and solid state [16,17,18,19,20] . There are many groups of foldamers differing in the type of backbone, with N,N’ ‐linked oligoureas being one example [21,22,23,24] . The N,N’ ‐disubstituted urea group may exist in trans,trans , cis,trans or cis,cis conformations (Figure 1), as the barrier of rotation is lower than for the corresponding amides [25,26,27] .…”

Section: Introductionmentioning

confidence: 99%

“…[16,17,18,19,20] There are many groups of foldamers differing in the type of backbone, with N,N'-linked oligoureas being one example. [21,22,23,24] The N,N'-disubstituted urea group may exist in trans,trans, cis,trans or cis,cis conformations (Figure 1), as the barrier of rotation is lower than for the corresponding amides. [25,26,27] The preferred conformation strongly depends on the structure, but also on the conditions, such as the solvent and the concentration, with the trans,trans or cis,trans conformers being the most populated.…”

Section: Introductionmentioning

confidence: 99%

Structural Consequences of N‐Methylation of N‐Terminus in Oligourea Foldamers

2022

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Oligourea foldamers fold into 2.5‐helices. Most of the known modifications of the backbone, such as NH or CO group substitutions or incorporations of non‐canonical residues, do not change the conformational properties of the resulting oligourea oligomers. In this study, we examined the structural influence of the methyl group, substituting NH protons in one or two residues at the N‐terminus of the foldamer. Such N‐methylated oligoureas appear to be helically folded with helix parameters determined from the crystal structure being almost the same as for non‐methylated oligomers. Solution studies (CD, NMR) reveal that the backbone with N‐Me urea groups is more flexible, but the urea group is still predominantly in trans,trans conformation. N‐Methylation does not change the structural properties of oligourea foldamers, and thus may be a useful modification for modulating the strength of hydrogen bonds and intermolecular interactions.

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Urea based foldamers

Cited by 13 publications

References 76 publications

Helical Foldamers and Stapled Peptides as New Modalities in Drug Discovery: Modulators of Protein-Protein Interactions

Helical Foldamers and Stapled Peptides as New Modalities in Drug Discovery: Modulators of Protein-Protein Interactions

Design of Oligourea-Based Foldamers with Antibacterial and Antifungal Activities

Structural Consequences of N‐Methylation of N‐Terminus in Oligourea Foldamers

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