Exogenous nucleosome-binding molecules: a potential new class of therapeutic drugs

Constant changes in the structure of chromatin regulate gene expression. Molecules that bind to the nucleosome, the complex of DNA and histone proteins, are key modulators of chromatin structure. Conceptually, the nucleosome was first identified as a therapeutic target 14 years ago, when small molecules started to be elegantly designed for nucleosomal DNA binding. Concomitantly, emergent drugs that target enzymes that affect chromatin structure have been developed to a treat myriad of diseases, such as cancer. Here, we discuss the development of more complex molecules, such as peptides and peptidomimetics, to directly target the nucleosome surface to modulate chromatin structure. This new strategy presents great challenges that need to be overcome to develop the exogenous nucleosome-binding molecules (eNBMs) as therapeutic agents.