Chimeric (α/β + α)-Peptide Ligands for the BH3-Recognition Cleft of Bcl-x_L: Critical Role of the Molecular Scaffold in Protein Surface Recognition

摘要

Molecules that bind to specific protein surface sites are of fundamental interest, from the perpective of molecular recognition, and practical interest, from the perspective of medicine. Such molecules should disrupt specific protein-protein interactions, which are frequently associated with human diseases. Traditional "small molecule" approaches, very successful for enzyme inhibition, have been less productive for generation of protein-protein interaction antagonists, although some recent achievements are very impressive. We and others are interested in the prospect that unnatural oligomers with discrete folding propensities ("foldamers") might provide a rational and general basis for development of molecules that block protein-protein interactions. Here we explore this possibility in the context of Bcl-x_L/BH3 domain interactions, a system that is attractive for fundamental studies because considerable structural information is available.