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Pharmacol Ther. 2017 May;173:159-170. doi: 10.1016/j.pharmthera.2017.02.014. Epub 2017 Feb 7.

Targeting kinase signaling pathways with constrained peptide scaffolds.

Author information

1
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, United States.
2
Department of Pharmaceutical and Biomedical Sciences, College of Pharmacy, University of Georgia, Athens, GA 30602, United States. Electronic address: ekennedy@uga.edu.

Abstract

Kinases are amongst the largest families in the human proteome and serve as critical mediators of a myriad of cell signaling pathways. Since altered kinase activity is implicated in a variety of pathological diseases, kinases have become a prominent class of proteins for targeted inhibition. Although numerous small molecule and antibody-based inhibitors have already received clinical approval, several challenges may still exist with these strategies including resistance, target selection, inhibitor potency and in vivo activity profiles. Constrained peptide inhibitors have emerged as an alternative strategy for kinase inhibition. Distinct from small molecule inhibitors, peptides can provide a large binding surface area that allows them to bind shallow protein surfaces rather than defined pockets within the target protein structure. By including chemical constraints within the peptide sequence, additional benefits can be bestowed onto the peptide scaffold such as improved target affinity and target selectivity, cell permeability and proteolytic resistance. In this review, we highlight examples of diverse chemistries that are being employed to constrain kinase-targeting peptide scaffolds and highlight their application to modulate kinase signaling as well as their potential clinical implications.

KEYWORDS:

Constrained peptide; Kinase inhibitor; Peptide macrocycle; Stapled peptide

PMID:
28185915
PMCID:
PMC5407947
DOI:
10.1016/j.pharmthera.2017.02.014
[Indexed for MEDLINE]
Free PMC Article

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