Inhibitors of Protein Kinases and Protein Phosphates Contributors

Protein–protein interactions serve as the molecular engine that drives the formation and disassembly of intracellular signaling pathways. Antagonists of these interactions could play key roles as both biological reagents and therapeutic compounds. However, much of the early work in this area with peptides revealed that these species, in general, bind with modest affinity to their protein targets. In addition, when these studies first commenced nearly 20 years ago, the technology for the intracellular delivery of peptides and modified analogs thereof was rudimentary. In the intervening years, not only has this technology dramatically improved, but the global role that protein–protein interactions play in transducing intracellular signals has become simply too obvious to ignore. With the introduction of combinatorial library methods, it is now a simple matter to identify consensus sequences recognized by protein interaction domains. An array of strategies has now been developed to transform these otherwise modest binding consensus sequences into high-affinity ligands. These strategies include the design of high-affinity replacements for key amino acid residues in consensus peptides, the construction of HEP (2005) 167:11--44 Springer-Verlag 2005