Helical aromatic foldamer-based protein recognition

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Protein-protein and protein-nucleic acid interactions (PPIs and PNIs) are required for the regulation of cellular life. Inhibitors of these interactions provide useful pharmacological tools and candidates for therapeutic applications. However, PPIs or PNIs involve large molecular surface areas which makes it difficult for drug-like small molecules to act as efficient inhibitors. Artificial proteins or artificial nucleic acids identified by selection technologies are large enough and constitute suitable PPI or PNI inhibitors but they lack some advantages of synthetic molecules in particular their structural and metabolic stability. Our research group has been exploring an alternate approach that combines some benefits of both small molecules and artificial proteins: the design of large - protein-sized - synthetic molecules that adopt stable helical structures ("foldamers") and that selectively recognize and bind protein targets. Recent developments include the design of foldamers that mimic the B-DNA negative charge surface and inhibit some PNIs as well as the demonstration that short foldamers are tolerated as initiators for in vitro peptide translation by the ribosome. In this project, we propose to exploit these findings for the molecular recognition of proteins of importance in epigenetics. Epigenetics is a growing field concerned with characteristics and functions transmitted during cell division that are not encoded in the genetic material itself. Our objectives are: 1) to decipher the structural basis of interactions between the foldamer DNA charge surface mimics and proteins involved in DNA packaging (chromatin) and thereby establish a firm basis for structure-based foldamer-design; 2) to investigate how DNA-mimic foldamers may alter chromatin assembly and identify chromatin proteins that bind to the foldamer-based DNA mimics better than to DNA; 3) to identify hybrid foldamer-peptide macrocycles that bind to proteins involved in epigenetic processes, elucidate the structural basis of the interactions involved; and use that knowledge to improve their properties.