Investigation of the classical histone deacetylases and sirtuins using peptide technologies

Histone deacetylase (HDAC) enzymes are hydrolases that remove acyl-based modifications from the side chains of lysine residues in our proteome. Originally named after their first identified substrates, the acetylated lysine residues in histone proteins, it has now become evident that individual isozymes of the HDAC class have different protein targets, cellular localization, and ε-N-acyllysine substrate specificities. To help elucidate the activities of the different HDACs, researchers have developed a variety of peptide-based tools, providing mechanistic insights and substrate preferences of the HDACs. Due to their central regulatory roles, HDACs have been investigated as drug targets, resulting in several drugs approved for clinical use, including the naturally occurring peptide, romidepsin, spurring the interest in peptide-based inhibitors. In this review, we provide a concise overview of important discoveries enabled by peptide chemistry in the HDAC field and discuss the future potential of high-throughput peptide technologies for HDAC profiling and inhibitor discovery.