New Design Strategies for Ligands That Target Protein Kinase Mediated Protein Protein Interactions

D. S. Lawrence

Department of Biochemistry, The Albert Einstein College of Medicine, 1300 Morris Park Ave, Bronx, NY 10461, USA [email protected]

1 Introduction 12

2 Identification of Consensus Sequences 13

2.1 Degradation of Protein Ligands 13

2.2 Synthetic Peptide Libraries 14

2.3 Phage Display 15

3 The Protein-Binding Domains of Protein Kinases 16

4 Strategies for the Acquisition of Potent and Selective Peptide-Based Inhibitors of Protein Kinases 19

4.1 Mimetics of Key Residues in Consensus Sequence Peptides 20

4.1.1 Serine Analogs 20

4.1.2 Tyrosine Analogs 22

4.1.3 Phosphotyrosine Analogs 27

4.1.4 Proline Analogs 28

4.2 Multidomain-Targeting Peptides 29

4.3 Structural Modification of Consensus Sequence Peptides 33

4.3.1 Conformationally Biased Peptides 33

4.3.2 Terminally Modified Peptides 35

4.3.3 Globally Modified Peptides 36

5 Summary 38

References 39

Abstract 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 pep-tides 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 multidomain-binding peptides, and the structural modification of consensus sequence peptides. In several of these instances, unprecedented affinity (<nM) and selectivity (>1,000-fold versus closely related protein targets) have been achieved.

Keywords Signal transduction ■ Antagonists of protein-protein interactions ■ Peptide-based inhibitors ■ Protein kinases and phosphatases ■ Combinatorial libraries ■ Amino acid analogs ■ Bivalent inhibitors ■ Structurally modified peptides

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