title: A Review of Stapled Peptides and Small Molecules to Inhibit Protein-Protein Interactions in Cancer.
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.
authors.affiliation: School of Bio Sciences and Technology, VIT University, Vellore 632014, Tamil Nadu, India. vidhyaiyer.v@vit.ac.in.
authors.forename: Vidhya V
authors.initials: VV
authors.lastname: Iyer
mesh_terms: D039642:Eukaryotic Initiation Factors / Q000737:chemistry / Q000378:metabolism; D006801:Humans; D008780:Methyltransferases / Q000737:chemistry / Q000378:metabolism; D009369:Neoplasms / Q000188:drug therapy / Q000473:pathology; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D057786:Peptidomimetics / Q000737:chemistry / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D054730:Protein Interaction Domains and Motifs / Q000187:drug effects*; D015398:Signal Transduction / Q000187:drug effects; D054852:Small Molecule Libraries / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism
chemical_list: D039642:Eukaryotic Initiation Factors; D010455:Peptides; D057786:Peptidomimetics; D054852:Small Molecule Libraries; D051176:beta Catenin; D008780:Methyltransferases