Rational design strategies for developing synthetic inhibitors of helical protein interfaces

Cellular function depends on highly specific interactions between biomolecules (proteins, RNA, DNA, and carbohydrates). A basic limitation of drug development is the inability of traditional "small-molecule" pharmaceuticals to specifically target large protein interfaces, many of which are desirable drug targets. α-Helices, ubiquitous elements of protein structures, play fundamental roles in many protein-protein interactions. Stable mimics of α-helices that can predictably disrupt these interactions would be invaluable as tools in molecular biology, and as leads in drug discovery. The past decade has seen exciting progress in the molecular design of these protein domain mimetics and their remarkable potential to inhibit challenging interactions. Key challenges in the field include identification of suitable targets and bioavailability of medium-sized molecules, which do not conform to empirical rules followed in traditional drug design. Stabilized α-helices bypass some of the strict limitations that have been placed on drug discovery. When designing potential drug candidates, medicinal chemists often adhere to the Lipinski rules, which stipulate that the molecular mass of a drug should not exceed 500 Da. Recent findings suggest that large synthetic α-helices can traffic into the cell and efficiently compete with cellular protein-protein interactions, contrary to predictions based on the Lipinski rules. Although these molecules have undoubtedly proven their value as probes for decoding biological complexity, the next big question is whether these molecules can become therapeutics. This chapter discusses the properties of protein-protein interactions, emerging rules for identifying protein targets and design criteria guiding construction of helix mimetics.