12-Helix Folding of Cyclobutane β-Amino Acid Oligomers

Fernandes, Carlos; Faure, Sophie; Pereira, Elisabeth; Théry, Vincent; Declerck, Valérie; Guillot, Régis; Aitken, David J.

doi:10.1021/ol101267u

Cited by 87 publications

(82 citation statements)

References 37 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…However, the far‐UV CD spectra of all α/β/γ‐peptides 1 – 8 were recorded in 0.2 m m MeOH solution and each showed a marked Cotton effect, presenting a minimum around 206 nm and a maximum around 224 nm (Figure 2 d). These data compare closely with the methanol‐solution signatures of both the 13‐helix adopted by β/γ‐peptides and the 12‐helix adopted by β‐peptides,40, 41, 42 thus suggesting that α/β/γ‐peptides 1 – 8 adopt a similar folded conformation in the same solvent. Collectively, the NMR, IR, and CD data provide strong evidence that α/β/γ‐peptides 1 – 8 are capable of adopting a hydrogen‐bonded helical conformation in hydrogen‐bonding and non‐hydrogen‐bonding solvents.…”

supporting

confidence: 66%

An α‐Helix‐Mimicking 12,13‐Helix: Designed α/β/γ‐Foldamers as Selective Inhibitors of Protein–Protein Interactions

et al. 2016

Self Cite

View full text Add to dashboard Cite

A major current challenge in bioorganic chemistry is the identification of effective mimics of protein secondary structures that act as inhibitors of protein–protein interactions (PPIs). In this work, trans‐2‐aminocyclobutanecarboxylic acid (tACBC) was used as the key β‐amino acid component in the design of α/β/γ‐peptides to structurally mimic a native α‐helix. Suitably functionalized α/β/γ‐peptides assume an α‐helix‐mimicking 12,13‐helix conformation in solution, exhibit enhanced proteolytic stability in comparison to the wild‐type α‐peptide parent sequence from which they are derived, and act as selective inhibitors of the p53/hDM2 interaction.

show abstract

supporting

confidence: 66%

An α‐Helix‐Mimicking 12,13‐Helix: Designed α/β/γ‐Foldamers as Selective Inhibitors of Protein–Protein Interactions

et al. 2016

Self Cite

View full text Add to dashboard Cite

show abstract

“…Thel ower solubility of peptides 5-8 in aprotic solvents (< 1mm in CDCl 3 )precluded similar NMR and IR studies for these compounds.However,the far-UV CD spectra of all a/b/ g-peptides 1-8 were recorded in 0.2 mm MeOH solution and each showed am arked Cotton effect, presenting am inimum around 206 nm and am aximum around 224 nm (Figure 2d). These data compare closely with the methanol-solution signatures of both the 13-helix adopted by b/g-peptides and the 12-helix adopted by b-peptides, [40][41][42] thus suggesting that a/b/g-peptides 1-8 adopt asimilar folded conformation in the same solvent. Collectively,t he NMR, IR, and CD data provide strong evidence that a/b/g-peptides 1-8 are capable of adopting ah ydrogen-bonded helical conformation in hydrogen-bonding and non-hydrogen-bonding solvents.…”

supporting

confidence: 64%

An α‐Helix‐Mimicking 12,13‐Helix: Designed α/β/γ‐Foldamers as Selective Inhibitors of Protein–Protein Interactions

et al. 2016

Self Cite

View full text Add to dashboard Cite

Amajor current challenge in bioorganic chemistry is the identification of effective mimics of protein secondary structures that act as inhibitors of protein-protein interactions (PPIs). In this work, trans-2-aminocyclobutanecarboxylic acid (tACBC) was used as the key b-amino acid component in the design of a/b/g-peptides to structurally mimic anative a-helix. Suitably functionalized a/b/g-peptides assume an a-helixmimicking 12,13-helix conformation in solution, exhibit enhanced proteolytic stability in comparison to the wild-type a-peptide parent sequence from which they are derived, and act as selective inhibitors of the p53/hDM2 interaction.Foldamers are unnatural oligomers that adopt well-defined secondary and tertiary conformations. [1][2][3][4] As bioinspired structures,s ome of them have been validated as useful reagents to modulate (therapeutically important) biological processes and systems, [4][5][6][7][8][9] and others as building blocks for use in synthetic biology [10][11][12][13][14] or the construction of functional materials. [15,16] Ap articularly fertile area is centred on the search for foldamers that mimic natural secondary structures (specifically a-helices) and thereby act as inhibitors of protein-protein interactions (PPIs). [17][18][19][20][21] However,t here is still aneed to develop ligands that more effectively mimic the conformation and molecular recognition capabilities of the ahelix. Herein, we present the bottom-up design of hybrid a/b/ g-peptides that assume an a-helix-mimicking 12,13-helical conformation and function as effective inhibitors of the p53/ hDM2 interaction.Amongst am ultitude of foldamer classes where structural/ conformational determinants have been mapped, [1][2][3][4] bpeptides and hybrid a/b-peptides,inwhich b-amino acids are dispersed along an a-peptide backbone,c an inhibit a-helixmediated protein-protein interactions [22][23][24][25][26][27][28][29] and mimic the structure and the function of protein surfaces. [30,31] Nonetheless foldamers that more accurately mimic the topology and topography of the a-helix might prove advantageous in comparison to b-and a/b-peptides,which may not fully mimic the spatial presentation of a-helix side chains.S everal foldamer scaffolds have been hypothesized to have potential for the inhibition of a-helix-mediated PPIs, [32][33][34][35] but they have not yet been shown to do so experimentally. b/g-Peptide sequences fall into this category:adipeptide of b-a nd gresidues forming a13-membered hydrogen-bonded ring (C = O(i)-NH(i + 3)) is analogous to atripeptide of a-amino acids forming the 13-membered hydrogen-bonded ring (C = O(i)-NH(i + 4)) of the native a-helix. The1 3-helix represents am ore accurate topographical mimic of the natural a(4 13 )-helix and represents an attractive template on which to elaborate inhibitors of protein-protein interactions.W hilst both the Gellman and Balaram groups have previously demonstrated that the introduction of b and g residues is tolerated within sequences of a-amino acids,which re...

show abstract

“…The homopolymer of the cis stereoisomer of 2-aminocyclobutane-1-carboxylic acid (ACBA), (R,S)-1, forms exclusively a six-membered hydrogen-bonded foldamer (e.g. [Z 6 P ], Torres et al 2010), while that of thetrans (S,S) adopts a helical fold (Fernandes et al 2010). In ACBA polymers of mixed chirality, a structural transition between the aforementioned twofold was hypothesized for the cis-trans isomer, never reported previously.…”

mentioning

confidence: 99%

Foldamers of β-peptides: conformational preference of peptides formed by rigid building blocks. The first MI-IR spectra of a triamide nanosystem

et al. 2013

View full text Add to dashboard Cite

IntroductionAlthough dynamic on a large timescale of motion, some biologically active polyamide nanosystems adopt welldefined 3D structures in a time average manner, called as globular proteins; a given name reflecting to their overall shape. Other proteins called intrinsically unstructured or dynamic (IUP or IDP) are reluctant to present such an easy to characterize structural ensemble, nicknamed as proteins with random structures. Thus, proteins exist in most phases as conformational ensembles presenting lower, while in other environment higher time average deviation from their average 3D folds. The α-amino acid sequence modification of these inherently dynamic polyamide systems can lower, or increase the amplitude and frequency of such internal motion, making the protein fold less or more -mobile‖. The chemical constitution (α) and the stereochemistry (L) of proteogenic amino acid residues are under strict evolutional conservation. Unlike L-Proline, all the remaining 19 common residues in proteins have two adjacent backbone torsional angles, φ and ψ, of high rotational freedom followed by the inflexible ω. The scenario of two flexible followed by a fixed backbone torsional angles per residue determines primarily the folding ability of a proteogenic polypeptide. Cutting of a globular fold seldom results in secondary structural elements (e.g. α-helix, β-turn) of low internal dynamics! Typically the removal of any secondary structural element from its -natural environment‖ results in polypetides of very elevated internal dynamics, often characterized as unstructured subunits. However, bioengineering requires stable toolkits to design epitopes, matching complementary folds, individual foldamers, nano-lego elements etc. of traceable shape and of low internal mobility. Shedding light on folding and stability of secondary structural elements of peptides and proteins could help to design standalone foldamers. They could be composed of β-, α-and α/β-amino acid residues, the latter called chimera. A general expectation of foldamers is to present a single time average 3D-structure of lower internal dynamics over the large timescale of picoseconds to second. These fold optimized biocompatible and nonnatural peptides often have an increased proteolytic and metabolic stability and can fulfill diverse biological functions toward DNA, RNA, ATP, etc. The improved ability of β-peptides and thus β-foldamers to rapidly and spontaneously fold (

show abstract

12-Helix Folding of Cyclobutane β-Amino Acid Oligomers

Cited by 87 publications

References 37 publications

An α‐Helix‐Mimicking 12,13‐Helix: Designed α/β/γ‐Foldamers as Selective Inhibitors of Protein–Protein Interactions

An α‐Helix‐Mimicking 12,13‐Helix: Designed α/β/γ‐Foldamers as Selective Inhibitors of Protein–Protein Interactions

An α‐Helix‐Mimicking 12,13‐Helix: Designed α/β/γ‐Foldamers as Selective Inhibitors of Protein–Protein Interactions

Foldamers of β-peptides: conformational preference of peptides formed by rigid building blocks. The first MI-IR spectra of a triamide nanosystem

Contact Info

Product

Resources

About