Tuning Sulfur Oxidation States on Thioether‐Bridged Peptide Macrocycles for Modulation of Protein Interactions

Perell, Gabriella; Staebell, Rachel Lynn; Hairani, Mehrdad; Cembran, Alessandro; Pomerantz, William C.

doi:10.1002/cbic.201700222

Cited by 20 publications

(24 citation statements)

References 59 publications

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“…All peptides were synthesized using HOBT and HBTU coupling reagents according to published methods. 30 Following Fmoc deprotection of the final residue, the peptides were cleaved from the resin using a 95:2.5:2.5 TFA/TIPS/H 2 O mixture and stirred for 2 h. The peptide cleavage solution was separated from the resin, and the solution was concentrated under a stream of N 2 . The crude peptide was precipitated with ether, cooled to −20 °C for at least 15 min, and pelleted by centrifugation at 3000 g for 5 min at 4 °C.…”

Section: Methodsmentioning

confidence: 99%

Specific Acetylation Patterns of H2A.Z Form Transient Interactions with the BPTF Bromodomain

et al. 2017

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Post-translational lysine acetylation of histone tails affects both chromatin accessibility and recruitment of multifunctional bromodomain-containing proteins for modulating transcription. The bromodomain- and PHD finger-containing transcription factor (BPTF) regulates transcription but has also been implicated in high gene expression levels in a variety of cancers. In this report, the histone variant H2A.Z, which replaces H2A in chromatin, is evaluated for its affinity for BPTF with a specific recognition pattern of acetylated lysine residues of the N-terminal tail region. Although BPTF immunoprecipitates H2A.Z-containing nucleosomes, a direct interaction with its bromodomain has not been reported. Using protein-observed fluorine nuclear magnetic resonance (PrOF NMR) spectroscopy, we identified a diacetylation of H2A.Z on lysine residues 4 and 11, with the highest affinity for BPTF with a Kd of 780 µM. A combination of subsequent 1H NMR Carr–Purcell–Meiboom–Gill experiments and photo-cross-linking further confirmed the specificity of the diacetylation pattern at lysines 4 and 11. Because of an adjacent PHD domain, this transient interaction may contribute to a higher-affinity bivalent interaction. Further evaluation of specificity toward a set of bromodomains, including two BET bromodomains (Brd4 and BrdT) and two Plasmodium falciparum bromodomains, resulted in one midmicromolar affinity binder, PfGCN5 (Kd = 650 µM). With these biochemical experiments, we have identified a direct interaction of histone H2A.Z with bromodomains with a specific acetylation pattern that further supports the role of H2A.Z in epigenetic regulation.

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Section: Methodsmentioning

confidence: 99%

Specific Acetylation Patterns of H2A.Z Form Transient Interactions with the BPTF Bromodomain

et al. 2017

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“…In the context of α‐helix‐mediated PPIs, considerable effort has been exerted on developing methods for constraining (or “stapling”) peptides in an α‐helical conformation. This approach has been used to confer enhanced proteolytic stability, enhanced cell‐uptake and, in some cases, enhanced target affinity on constrained peptide sequences . We recently introduced a series of reagents and approaches for constraining peptides in a helical conformation .…”

Section: Figurementioning

confidence: 99%

Recognition of ASF1 by Using Hydrocarbon‐Constrained Peptides

et al. 2019

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Inhibiting the histone H3–ASF1 (anti‐silencing function 1) protein–protein interaction (PPI) represents a potential approach for treating numerous cancers. As an α‐helix‐mediated PPI, constraining the key histone H3 helix (residues 118–135) is a strategy through which chemical probes might be elaborated to test this hypothesis. In this work, variant H3 118–135 peptides bearing pentenylglycine residues at the i and i +4 positions were constrained by olefin metathesis. Biophysical analyses revealed that promotion of a bioactive helical conformation depends on the position at which the constraint is introduced, but that the potency of binding towards ASF1 is unaffected by the constraint and instead that enthalpy–entropy compensation occurs.

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“…These peptides were used to target the MLL‐KIX protein‐protein interaction. Although the addition of the oxidized sulfur atoms did not lead to increases in helicity, this method has potential to be used in an effort to modify the polarity of constrained peptides …”

Section: Tether Functionalizationmentioning

confidence: 99%

Recent structural advances in constrained helical peptides

Skowron

Speltz

Moore

2018

Medicinal Research Reviews

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Given the ubiquity of the ⍺-helix in the proteome, there has been much research in developing mimics of ⍺-helices, and most of this study has been toward developing proteinprotein interaction inhibitors. A common strategy for mimicking ⍺-helices has been through the use of constrained, helical peptides. The addition of a constraint typically provides for conformational and proteolytic stability and, in some cases, cell permeability. Some of the most well-known strategies included are lactam formation and hydrocarbon "stapling." Beyond those strategies, there have been many recent advances in developing constrained peptides. The purpose of this review is to highlight recent advances in the development of new helix-stabilizing technologies, constraint diversification strategies, tether diversification strategies, and combination strategies that create new bicyclic helical peptides. K E Y W O R D S alpha helix, helical peptides, peptide chemistry, protein-protein interactions 1 | INTRODUCTIONThere are a multitude of protein-protein interactions in the cell that are mediated by ⍺-helices, and in many disease states it would be advantageous to mimic features of an ⍺-helix with a small molecule or peptide. A common strategy for mimicking ⍺-helices has been through the use of constrained, helical peptides. 1-9 Doing so provides for conformational stability by reducing the number of degrees of freedom of the peptide and/or by facilitating ⍺-helical hydrogen bonding. This strategy also often provides for proteolytic stability: many proteases recognize an extended peptide conformation, but because of the conformational rigidity imparted by the constraint, helical peptides are not readily recognized by proteases that otherwise might recognize an Med Res Rev. 2019;39:749-770.wileyonlinelibrary.com/journal/med

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Tuning Sulfur Oxidation States on Thioether‐Bridged Peptide Macrocycles for Modulation of Protein Interactions

Cited by 20 publications

References 59 publications

Specific Acetylation Patterns of H2A.Z Form Transient Interactions with the BPTF Bromodomain

Specific Acetylation Patterns of H2A.Z Form Transient Interactions with the BPTF Bromodomain

Recognition of ASF1 by Using Hydrocarbon‐Constrained Peptides

Recent structural advances in constrained helical peptides

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