Isoxazole‐Derived Amino Acids are Bromodomain‐Binding Acetyl‐Lysine Mimics: Incorporation into Histone H4 Peptides and Histone H3

Abstract: A range of isoxazole‐containing amino acids was synthesized that displaced acetyl‐lysine‐containing peptides from the BAZ2A, BRD4 (1), and BRD9 bromodomains. Three of these amino acids were incorporated into a histone H4‐mimicking peptide and their affinity for BRD4 (1) was assessed. Affinities of the isoxazole‐containing peptides are comparable to those of a hyperacetylated histone H4‐mimicking cognate peptide, and demonstrated a dependence on the position at which the unnatural residue was incorporated. An isoxazole‐based alkylating agent was developed to selectively alkylate cysteine residues in situ. Selective monoalkylation of a histone H4‐mimicking peptide, containing a lysine to cysteine residue substitution (K12C), resulted in acetyl‐lysine mimic incorporation, with high affinity for the BRD4 bromodomain. The same technology was used to alkylate a K18C mutant of histone H3.

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• Location: Deutsche Nationalbibliothek Frankfurt am Main
• Extent: Online-Ressource
• Language: Englisch

References and Relationships

• Bibliographic citation: Isoxazole‐Derived Amino Acids are Bromodomain‐Binding Acetyl‐Lysine Mimics: Incorporation into Histone H4 Peptides and Histone H3 ; volume:128 ; number:29 ; year:2016 ; pages:8493-8497 ; extent:5 ; Angewandte Chemie ; 128, Heft 29 (2016), 8493-8497 (gesamt 5)

Contributors, Places and Time

• Creator: Sekirnik (née Measures), Angelina R. ; Hewings, David S. ; Theodoulou, Natalie H. ; Jursins, Lukass ; Lewendon, Katie R. ; Jennings, Laura E. ; Rooney, Timothy P. C. ; Heightman, Tom D. ; Conway, Stuart J.

Further information

• DOI: 10.1002/ange.201602908
• URN: urn:nbn:de:101:1-2022101408134836445341
• Rights: Open Access; Der Zugriff auf das Objekt ist unbeschränkt möglich.