End-capped α-helices as modulators of protein function

Mahon, Andrew B.; Arora, Paramjit S.

doi:10.1016/j.ddtec.2011.07.008

Cited by 39 publications

(39 citation statements)

References 39 publications

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“…Then ucleation strategy may maximize recognition specificity of the original sequence without compromising the molecular recognition surface. [5] Them ost successful helix nucleation strategy,n amely the hydrogen-bond surrogate (HBS) system, [4d, 6] features the replacement of ah ydrogen bond at the N-terminus by acovalent link. [7] Among different types of HBS systems,alkene-tethered HBS helices have been applied to various biologically relevant targets.…”

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confidence: 99%

“…[10] Other helix-nucleating templates with rigid carbonyl mimics [4a-c, 9] require multistep syntheses and bulky appendages,w hich limit further applications. [5] No nucleating template constructed by asimple side-chain-end crosslinking has been documented. Herein, we report afacile helix-nucleating template based on atethered aspartic acid at the N-terminus (Scheme 1).…”

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confidence: 99%

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Crosslinked Aspartic Acids as Helix‐Nucleating Templates

et al. 2016

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Described is a facile helix-nucleating template based on a tethered aspartic acid at the N-terminus [terminal aspartic acid (TD)]. The nucleating effect of the template is subtly influenced by the substituent at the end of the side-chain-end tether as indicated by circular dichroism, nuclear magnetic resonance, and molecular dynamics simulations. Unlike most nucleating strategies, the N-terminal amine is preserved, thus enabling further modification. Peptidomimetic estrogen receptor modulators (PERMs) constructed using this strategy show improved therapeutic properties. The current strategy can be regarded as a good complement to existing helix-stabilizing methods.

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confidence: 99%

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Crosslinked Aspartic Acids as Helix‐Nucleating Templates

et al. 2016

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“…Over the past several decades, various approaches, spanning non-covalent and covalent strategies, to reinforcing the bioactive helical conformation were developed17. Various non-covalent strategies have been used to stabilize peptide backbone toward the a-helical conformation, including helix-nucleating templates18192021 and introducing α, α-disubstituted amino acid, such as aminoisobutyric acid2223. While for covalent strategies, a common approach for inducing and stabilizing fixed secondary structure in peptides is by tethering two side chains on the same face of the helix via different cross-links.…”

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confidence: 99%

Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity

Zhang

Jiang

et al. 2016

Sci Rep

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Inducing α-helicity through side-chain cross-linking is a strategy that has been pursued to improve peptide conformational rigidity and bio-availability. Here we describe the preparation of small peptides tethered to chiral sulfoxide-containing macrocyclic rings. Furthermore, a study of structure-activity relationships (SARs) disclosed properties with respect to ring size, sulfur position, oxidation state, and stereochemistry that show a propensity to induce α-helicity. Supporting data include circular dichroism spectroscopy (CD), NMR spectroscopy, and a single crystal X-ray structure for one such stabilized peptide. Finally, theoretical studies are presented to elucidate the effect of chiral sulfoxides in inducing backbone α-helicity.

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“…Of these, hydrazones and thioethers with hydrocarbon cross-links formed by means of RCM (26; Figure 9 b) represent the most stabilizing scaffold. [241][242][243] The latter approach provides peptides with increased target affinity and bioavailability and allows a stabilization of the a-helical conformation without sacrificing side chains. [244][245][246] This is particularly interesting for helical peptides that have most of their residues involved in target recognition.…”

Section: N-terminal Capsmentioning

confidence: 99%

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

et al. 2015

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Protein–protein interactions (PPIs) are involved at all levels of cellular organization, thus making the development of PPI inhibitors extremely valuable. The identification of selective inhibitors is challenging because of the shallow and extended nature of PPI interfaces. Inhibitors can be obtained by mimicking peptide binding epitopes in their bioactive conformation. For this purpose, several strategies have been evolved to enable a projection of side chain functionalities in analogy to peptide secondary structures, thereby yielding molecules that are generally referred to as peptidomimetics. Herein, we introduce a new classification of peptidomimetics (classes A–D) that enables a clear assignment of available approaches. Based on this classification, the Review summarizes strategies that have been applied for the structure-based design of PPI inhibitors through stabilizing or mimicking turns, β-sheets, and helices.

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End-capped α-helices as modulators of protein function

Cited by 39 publications

References 39 publications

Crosslinked Aspartic Acids as Helix‐Nucleating Templates

Crosslinked Aspartic Acids as Helix‐Nucleating Templates

Chiral Sulfoxide-Induced Single Turn Peptide α-Helicity

Structure‐Based Design of Inhibitors of Protein–Protein Interactions: Mimicking Peptide Binding Epitopes

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