Structure of a Complex Formed by a Protein and a Helical Aromatic Oligoamide Foldamer at 2.1 Å Resolution

Buratto, J.; Colombo, Cinzia; Stupfel, Marine; Dawson, Simon J.; Dolain, Christel; d’Estaintot, Béatrice Langlois; Fischer, Lucile; Granier, T.; Laguerre, Michel S.; Gallois, B.; Huc, Ivan

doi:10.1002/ange.201309160

Cited by 24 publications

(28 citation statements)

References 70 publications

(39 reference statements)

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“…Hence, no real CD curves can be measured for these foldamers, but upon stable binding the equilibrium is shifted toward a given helical structure and considerable increases are detected in the CD signals. The interactions have been investigated in X-ray crystallization studies too, which revealed surprising protein--foldamer, foldamer--foldamer and protein--protein interaction patterns [139]. Another approach was used in the application of aromatic oligoamides as molecular hosts for sugar encapsulation: highly selective fructose complexors were created (Figure 4) [140].…”

Section: Aromatic Oligoamidesmentioning

confidence: 99%

“…Human carbonic anhydrase was effectively blocked by aromatic oligoamides. A very spectacular method was used to detect foldamer--protein interactions [139]. Aromatic oligoamides are known to form helical structures, but they undergo helical interconversion, which allows the simultaneous presence of both left-and right-handed helices.…”

Section: Aromatic Oligoamidesmentioning

confidence: 99%

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An overview of peptide and peptoid foldamers in medicinal chemistry

Mándity¹,

Fülöp²

2015

Expert Opinion on Drug Discovery

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Various new foldamers have been created with a range of structures and biological applications. Membrane-acting antibacterial foldamers have been introduced. A general property of these structures is their amphiphilic nature. The amphiphilicity can be stationary or induced by the membrane binding. Cell-penetrating foldamers have been described which serve as cargo molecules, and foldamers have been used as autophagy inducers. Anti-Alzheimer compounds too have been created and the greatest breakthrough was attained via the modification of protein-protein interactions. This can serve as the chemical and pharmaceutical basis for the relevance of foldamers in the future.

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Section: Aromatic Oligoamidesmentioning

confidence: 99%

Section: Aromatic Oligoamidesmentioning

confidence: 99%

An overview of peptide and peptoid foldamers in medicinal chemistry

Mándity¹,

Fülöp²

2015

Expert Opinion on Drug Discovery

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“…We previously used human carbonic anhydrase II (HCA) as a model system because this protein is known to crystallize easily—the Protein Data Bank contains over 500 crystal structures—and because synthetically accessible nanomolar ligands derived from aromatic sulfonamides exist that can be appended to a foldamer and ensure a non‐covalent yet tight linkage to HCA. In a recent report, we described the synthesis of short helical foldamers based on quinolinecarboxamides, each having an appended HCA ligand . The foldamers did not contain any stereogenic center and initially existed as racemic mixtures of right‐ ( P ) or left‐handed ( M ) helices.…”

Section: Introductionmentioning

confidence: 99%

“…The foldamers did not contain any stereogenic center and initially existed as racemic mixtures of right‐ ( P ) or left‐handed ( M ) helices. However, when the foldamers were confined to the HCA surface through binding of the ligands to the HCA active site, interactions were detected by circular dichroism (CD), which revealed a helix handedness bias for some foldamers, induced by preferential interactions of either the P or M helix with the inherently chiral protein surface . By using this method, compound 1 (Figure ) was identified as having a strong preference for P ‐handedness when linked to HCA.…”

Section: Introductionmentioning

confidence: 99%

Solution Observation of Dimerization and Helix Handedness Induction in a Human Carbonic Anhydrase–Helical Aromatic Amide Foldamer Complex

et al. 2016

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The design of synthetic foldamers to selectively bind proteins is currently hindered by the limited availability of molecular data to establish key features of recognition. Previous work has described dimerization of human carbonic anhydrase II (HCA) through self-association of a quinoline oligoamide helical foldamer attached to a tightly binding HCA ligand. A crystal structure of the complex provided atomic details to explain the observed induction of single foldamer helix handedness and revealed an unexpected foldamer-mediated dimerization. Here, we investigated the detailed behavior of the HCA-foldamer complex in solution by using NMR spectroscopy. We found that the ability to dimerize is buffer-dependent and uses partially distinct intermolecular contacts. The use of a foldamer variant incapable of self-association confirmed the ability to induce helix handedness separately from dimer formation and provided insight into the dynamics of enantiomeric selection.

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“…[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).…”

mentioning

confidence: 99%

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

et al. 2016

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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...

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Structure of a Complex Formed by a Protein and a Helical Aromatic Oligoamide Foldamer at 2.1 Å Resolution

Abstract: Scheme 1. a) Inhibitor constructs; b) Q Xxx monomers; c) Inh-Q n foldamers synthesized by SPS. Angewandte Chemie 903

Cited by 24 publications

References 70 publications

An overview of peptide and peptoid foldamers in medicinal chemistry

An overview of peptide and peptoid foldamers in medicinal chemistry

Solution Observation of Dimerization and Helix Handedness Induction in a Human Carbonic Anhydrase–Helical Aromatic Amide Foldamer Complex

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

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