Peptide Technologies in the Development of Chemical Tools for Chromatin-Associated Machinery

Discerning a mechanistic understanding of the cause-and-effect relationships between chromatin post-translational modifications (PTMs) and DNA accessibility for replication, transcription, and repair is an elusive goal being pursued using molecular and cellular biology, biochemistry, and more recently chemical inhibition. Chemical intervention of the chromatin-associated complexes that regulate PTM maintenance and chromatin structure faces numerous challenges due to the broad surface-groove interactions between many of these proteins and histones; yet, the increasing interest in understanding chromatin-modifying complexes suggests tractable lead compounds will be critical for elucidating the mechanisms of chromatin dysregulation in disease states and validating the druggability of these domains. Peptides and peptidomimetics afford several advantages to efficient inhibitor development including a rational starting point, modular assembly, and retention of secondary structure. Numerous peptide technologies have been employed in the chromatin field to characterize substrate interactions, evaluate ligand selectivity, and optimize potent peptidomimetic inhibitors. We describe the progress and advantages of these efforts, and provide a perspective on their implications for future chemical probe and drug discovery efforts. Drug Dev Res 78 : 300-312, 2017. (c) 2017 Wiley Periodicals, Inc.