New β-Strand Templates Constrained by Huisgen Cycloaddition

Pehere, Ashok Dattatray; Abell, Andrew D.

doi:10.1021/ol3002199

Cited by 44 publications

(32 citation statements)

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“…S1 and S2), indicative of a β-strand conformation. 17 Furthermore, 1 H NMR J NHCαH coupling constants consistent with a β-strand structure 18 were observed for these peptides. The conformations of 3 and 4 were confirmed as 3 10 -helical, based on observed CαH(i) to NH(i+1) and medium range CαH(i) to NH(i+2) ROESY correlations 5 ( Fig.…”

Section: Resultsmentioning

confidence: 78%

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Exploiting the interplay of quantum interference and backbone rigidity on electronic transport in peptides: a step towards bio-inspired quantum interferometers

Horsley

Abell

2017

Mol. Syst. Des. Eng.

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Deposition and sharing rightsWhen the author accepts the licence to publish for a journal article, he/she retains certain rights concerning the deposition of the whole article. This table summarises how you may distribute the accepted manuscript and version of record of your article. Electron transfer in peptides provides an opportunity to mimic nature for applications in bio-inspired molecular electronics. However, quantum interference effects, which become significant at the molecular level, have yet to be addressed in this context. Electrochemical and theoretical studies are reported on a series of cyclic and linear peptides of both β-strand and helical conformation, to address this shortfall and further realize the potential of peptides in molecular electronics. The introduction of a side-bridge into the peptides provides both additional rigidity to the backbone, and an alternative pathway for electron transport. Electronic transport studies reveal an interplay between quantum interference and vibrational fluctuations. We utilize these findings to demonstrate two distinctive peptide-based quantum interferometers, one exploiting the tunable effects of quantum interference (β-strand) and the other regulating the interplay between the two phenomena (310-helix).

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Section: Resultsmentioning

confidence: 78%

“…2a). Peptides 5 and 6 were confirmed as β-strand, with CαH(i) to NH(i+1), CβH(i) to NH(i+1) and sequential NH(i) to NH(i+1) ROESY correlations evident 17 ( Fig. S5 and S6).…”

Section: Resultsmentioning

confidence: 95%

Exploiting the interplay of quantum interference and backbone rigidity on electronic transport in peptides: a step towards bio-inspired quantum interferometers

Horsley

Abell

2017

Mol. Syst. Des. Eng.

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“…All this work is based on an ability to define and control the shape or conformation of peptides. [20][21][22] …”

Section: Resultsmentioning

confidence: 99%

The Influence of Secondary Structure on Electron Transfer in Peptides

Horsley

2013

Aust. J. Chem.

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A series of synthetic peptides containing 0-5 a-aminoisobutyric acid (Aib) residues and a C-terminal redox-active ferrocene was synthesised and their conformations defined by NMR and circular dichroism. Each peptide was separately attached to an electrode for subsequent electrochemical analysis in order to investigate the effect of peptide chain length (distance dependence) and secondary structure on the mechanism of intramolecular electron transfer. While the shorter peptides (0-2 residues) do not adopt a well defined secondary structure, the longer peptides (3-5 residues) adopt a helical conformation, with associated intramolecular hydrogen bonding. The electrochemical results on these peptides clearly revealed a transition in the mechanism of intramolecular electron transfer on transitioning from the ill-defined shorter peptides to the longer helical peptides. The helical structures undergo electron transfer via a hopping mechanism, while the shorter ill-defined structures proceeded via an electron superexchange mechanism. Computational studies on two b-peptides PCB-(b 3 Val-b 3 Ala-b 3 Leu) n -NHC(CH 3 ) 2 OOtBu (n ¼ 1 and 2; PCB ¼ p-cyanobenzamide) were consistent with these observations, where the n ¼ 2 peptide adopts a helical conformation and the n ¼ 1 peptide an ill-defined structure. These combined studies suggest that the mechanism of electron transfer is defined by the extent of secondary structure, rather than merely chain length as is commonly accepted.

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“…Head-to-tail lactamization is the most common method to synthesize cyclic peptides (34)(35)(36). Internal disulfide bonding is also used (37,38), as are newer techniques such as ring-closing olefin metathesis (39) and catalyzed cycloaddition of azides to alkynes (40)(41)(42). These procedures rely on judicious use of protecting groups and/or tailored amino acid residues (Fig.…”

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confidence: 99%

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

Lawson

Rose

Harran

2013

Proc. Natl. Acad. Sci. U.S.A.

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Peptide-protein interactions are important mediators of cellularsignaling events. Consensus binding motifs (also known as short linear motifs) within these contacts underpin molecular recognition, yet have poor pharmacological properties as discrete species. Here, we present methods to transform intact peptides into stable, templated macrocycles. Two simple steps install the template. The key reaction is a palladium-catalyzed macrocyclization. The catalysis has broad scope and efficiently forms large rings by engaging native peptide functionality including phenols, imidazoles, amines, and carboxylic acids without the necessity of protecting groups. The tunable reactivity of the template gives the process special utility. Defined changes in reaction conditions markedly alter chemoselectivity. In all cases examined, cyclization occurs rapidly and in high yield at room temperature, regardless of peptide composition or chain length. We show that conformational restraints imparted by the template stabilize secondary structure and enhance proteolytic stability in vitro. Palladium-catalyzed internal cinnamylation is a strong complement to existing methods for peptide modification. S ynthetic peptides and peptidomimetics play wide-ranging roles in pharmacology and drug discovery. Interest in these substances continues to grow, particularly as medicinal chemistry pushes further into control of cellular-signaling events mediated by protein-protein interactions (PPIs) (1-3). The subset of socalled "druggable" PPIs includes those mediated by consensus peptides, where binding determinants are localized within defined motifs (4-8). Experimental data as well as computational/ bioinformatic efforts (9-11) to identify "short linear motifs" within signaling proteins suggest that the number of druggable PPIs has been underestimated (12, 13). Considerable opportunity exists for new chemistry in this area (14). Synthetic peptides that target "hot spots" on protein surfaces are a logical entry to drug-discovery programs (15-19). However, native peptides generally have poor pharmacological properties (20). Modifications that offset those limitations while stably recapitulating proteinbinding conformations are of considerable interest (14,(21)(22)(23).Ring-forming reactions are prominent among alterations found to improve the stability and performance of peptides (24-27). They find broad utility in synthesis and, increasingly, in combination with phage, ribosome, and mRNA display technologies (28-32). Relative to their acyclic counterparts, cyclic peptides have more defined conformations and are less prone to aggregate (33). Head-to-tail lactamization is the most common method to synthesize cyclic peptides (34-36). Internal disulfide bonding is also used (37, 38), as are newer techniques such as ring-closing olefin metathesis (39) and catalyzed cycloaddition of azides to alkynes (40-42). These procedures rely on judicious use of protecting groups and/or tailored amino acid residues (Fig. 1A) (43, 44). Careful attention must be paid to...

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New β-Strand Templates Constrained by Huisgen Cycloaddition

Cited by 44 publications

References 33 publications

Exploiting the interplay of quantum interference and backbone rigidity on electronic transport in peptides: a step towards bio-inspired quantum interferometers

Exploiting the interplay of quantum interference and backbone rigidity on electronic transport in peptides: a step towards bio-inspired quantum interferometers

The Influence of Secondary Structure on Electron Transfer in Peptides

Template-constrained macrocyclic peptides prepared from native, unprotected precursors

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