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Current Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 0929-8673
ISSN (Online): 1875-533X

Review Article

A Review of Stapled Peptides and Small Molecules to Inhibit Protein–Protein Interactions in Cancer

Author(s): Vidhya V. Iyer

Volume 23, Issue 27, 2016

Page: [3025 - 3043] Pages: 19

DOI: 10.2174/0929867323666160627103134

Price: $65

Abstract

Disruption of binding of two or more molecules to a protein surface is a common basis of inhibition of many biological activities. Smallmolecule inhibitors, antibodies, proteins, and peptidomimetics have been examined as ways to antagonize receptor activity. The peptide α-helix plays a crucial role in the function of many proteins. Hence, much effort has been invested in mimicking α-helices at the binding interface of two proteins to competitively inhibit their interactions. Peptide stapling involves choosing two amino acids on the same face of a native peptide sequence for substitution with non-native amino acids whose side chains can be “stapled” together. The focus of this review is to survey the prevalence in literature of stapled peptides and small-molecule antagonists of interactions of selected mammalian cancer targets, such as β-catenin, BH3-only members of the Bcl-2 family of proteins, eIF4E/G, estrogen receptor complexes, EZH2, Mdm2, Notch, p110α, and survivin. The increasing interest in protein targets currently considered to be “undruggable” with greater selectivity for existing targets, with the goal of overcoming the omnipresent problem of resistance, could be served well by utilizing information about protein–protein interactions to develop both small-molecule and stapled peptide inhibitors.

Keywords: Small-molecule antagonists, cancer, protein–protein interactions, stapled peptides, peptidomimetics, alpha-helix.


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