Isoxazole-derived amino acids are bromodomain-binding acetyl-lysine mimics: incorporation into histone H4 peptides and histone H3

Journal article

A range of isoxazole-containing amino acids was synthesized, which displace 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 isoxazolecontaining 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.

Authors: Conway, S; Sekirnik, A; Hewings, D; Theodoulou, N; Jursins, L

• Publication status: Published
• Peer review status: Peer reviewed
• Publisher: Wiley
• Journal: Angewandte Chemie International Edition
• Volume: 55
• Issue: 29
• Pages: 8353–8357
• Publication date: 2016-06-06
• Acceptance date: 2016-05-10
• DOI: 10.1002/anie.201602908
• EISSN: 1521-3773
• ISSN: 1433-7851
• Keywords: alkylation; protein modifications; protein-protein interactions; bromodomain; acetyl-lysine