Title:A Review of Stapled Peptides and Small Molecules to Inhibit Protein–Protein Interactions in Cancer
Volume: 23
Issue: 27
Author(s): Vidhya V. Iyer
Affiliation:
Keywords:
Small-molecule antagonists, cancer, protein–protein interactions, stapled peptides, peptidomimetics,
alpha-helix.
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.
