Although a few exceptions are known, in general, conventional peptides display modest affinities and poor selectivities for the protein interaction domains contained within protein kinases. Biological systems appear to have little need for high-affinity ligands for active sites, SH2, SH3, LIM, PDZ, and other protein-interaction domains due to the transient nature of signaling pathways. However, it is abundantly clear that biological systems have mastered the issue of selectivity. Selective expression of only certain protein ki-nases in specific cell types, or at precise intervals during the lifetime of the cell, offers one means to navigate the tricky waters of intracellular selectivity. Spatial segregation of protein kinases to specific intracellular sites represents another means by which selectivity can be achieved. Finally, given the comparatively large size of these proteins, and their correspondingly well-defined structures, selectivity may simply be attained via a highly precise three-dimensional choreography of interactions between binding partners. Consequently, the design of potent and selective artificial antagonists of protein-protein interactions represents a significant challenge, albeit an exciting one. The primary advantage enjoyed by the chemist is that he or she is not restricted to the 20 standard amino acids designated by the genetic code.
The acquisition of agents that target protein-protein interaction sites has the potential to be relatively straightforward. Consensus sequences are easy to identify. However, it is necessary to develop the tools and/or strategies that can convert peptides containing these sequences into agents that recapitulate the high selectivities observed in biochemical pathways while significantly surpassing the affinities that intracellular binding partners display for one another. The tools and strategies to achieve the twin goals of potency and selectivity, within the framework of relatively small ligands (cf., proteins), are outlined below in three separate, but interrelated sections.
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