Peptide-based inhibitors of epigenetic proteins

Epigenetic drug discovery has become an integral part of medicinal chemistry in the past two decades. Targeting epigenetic proteins-enzymes that modify histone proteins and DNA (writers and erasers) and proteins that recognize such modifications (readers)-has been firmly established as a medicinal strategy for treatment of many human diseases, including cancer and neurological disorders. In this chapter, we systematically describe peptide-based inhibitors of structurally and functionally diverse classes of epigenetic proteins. We show that epigenetic writers, such as DNA methyltransferases, histone methyltransferases and histone acetyltransferases, can be efficiently inhibited by peptides possessing nonproteinogenic amino acids. Moreover, the activity of epigenetic erasers, including TET enzymes, histone demethylases, and histone deacetylases, can be selectively modulated by diverse linear and cyclic peptides. Furthermore, we discuss chromatin-binding epigenetic reader proteins that can be inhibited by histone-mimicking peptides. Overall, this chapter highlights that peptides provide an important molecular platform for epigenetic drug discovery programmes in academia and industry.