Incorporation of Butyryl-Lysine into Phage-Displayed Peptide Libraries

There are several epigenetic reader proteins that recognize butyrylated lysine residues, yet the majority peptide probes have been limited to histone-based substrates. Development of selective peptide substrates will play a key role in studying these proteins and in developing inhibitors of therapeutic potential. We have previously reported a strategy to incorporate N^ε-butyryl-L-lysine into phage-displayed peptide libraries that was used to identify inhibitors for the ENL YEATS domain. Here, we describe the production of phage-displayed peptide libraries that contain butyrylated lysine residues and their subsequent use to direct phage selections toward the active sites of epigenetic proteins. We envision the technique can be applicable to performing phage selections toward many different epigenetic readers, writers, and erasers implicated in a variety of cellular processes and diseases.