Abstract
α-Helices often recognize their target proteins at protein–protein interfaces through more than one recognition face. This review describes the state-of-the-art in the design of non-peptidic α-helix mimetics that reproduce functionality from multiple faces of an α-helix.
Highlights
Protein–protein interactions (PPIs) are involved in an array of crucial cellular processes that include differentiation, apoptosis, signal transduction and transcription [1,2,3]
PPIs boast solvent-exposed, large, flat and predominantly hydrophobic interfacial areas that comprise non-contiguous contact points, indicating that large, Biology 2015, 4 hydrophobic molecules might be mandatory for effective disruption [1]
Despite the large interfacial areas involved in PPIs, much of the free energy of binding is attributed to “hot spots”, smaller domains within the PPI that are more tractable to low-molecular-weight ligand design [11]. One such subset of PPIs is described by those that are mediated by α-helices, wherein key residues projected from the helix recognize hot spots in the target protein [12,13,14]. α-Helices are found at the interfaces of almost two-thirds of the PPIs found in the Protein Data Bank (PDB), demonstrating their significance in protein–protein recognition, and around half of these involve the helix utilizing a single recognition face [12]
Summary
Protein–protein interactions (PPIs) are involved in an array of crucial cellular processes that include differentiation, apoptosis, signal transduction and transcription [1,2,3]. Despite the large interfacial areas involved in PPIs, much of the free energy of binding is attributed to “hot spots”, smaller domains within the PPI that are more tractable to low-molecular-weight ligand design [11] One such subset of PPIs is described by those that are mediated by α-helices, wherein key residues projected from the helix recognize hot spots in the target protein [12,13,14]. Since preorganization is considered to enhance the free energy of binding owing to a reduced entropic penalty, the focus of this review is multi-sided helix mimetics that, through covalent and/or non-covalent bonds, are preorganized to reproduce functionality on multiple faces, in contrast to the those structures in Figure 3 that are designed to mimic only one face of an α-helix
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