Peptide Inhibitors Targeting Protein Kinases

Hagit      Eldar-Finkelman; Miriam      Eisenstein

Abstract

Phosphorylation by protein kinases is a central theme in biological systems. Aberrant protein kinase activity has been implicated in a variety of human diseases, therefore, modulation of kinase activity represents an attractive therapeutic approach for the treatment of human illnesses. Development and design of specific inhibitors for protein kinases thus became a major strategy in many drug discovery programs. Inhibition of protein kinase activity may be achieved by blocking the phosphorylation activity or by disrupting protein-protein interactions. Peptides that can mimic most truly these regulatory modes are favorite choice for protein kinase-targeting. Here we focus on important motifs regulating the protein kinase signaling network and described how they may be exploited for peptide drug design. Protein kinases are important regulators of most, if not all, biological processes. Their abnormal activity has been implicated as causal factors in many human diseases, including cancer, diabetes and neurodegenerative disorders [1-3]. Protein kinases are thus attractive targets for drug design and compounds that manipulate their cellular activity are of enormous therapeutic potential. With a target in hand, medicinal chemists can generate low molecular weight compounds that bind the target with high affinity and alter its biological behavior. In many cases, however, drugs fail as they lack appropriate pharmaceutical properties and are of limited specificity resulting in unfavorable side effects. Under these circumstances, the use of peptides, which copy ‘natural’ motifs that specifically influence kinase activity and/or its intracellular interactions with cognate partners, may be a promising approach for selective inhibition of protein kinases. In this review we focus on the strategies to design such peptide inhibitors, focusing mainly on the serine/threonine protein kinase family.

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