Inhibition of α-helix-mediated protein–protein interactions using designed molecules

Abstract

Inhibition of protein–protein interactions (PPIs) represents a significant challenge because it is unclear how they can be effectively and selectively targeted using small molecules. Achieving this goal is critical given the defining role of these interactions in biological processes. A rational approach to inhibitor design based on the secondary structure at the interface is the focus of much research, and different classes of designed ligands have emerged, some of which effectively and selectively disrupt targeted PPIs. This Review discusses the relevance of PPIs and, in particular, the importance of α-helix-mediated PPIs to chemical biology and drug discovery with a focus on designing inhibitors, including constrained peptides, foldamers and proteomimetic-derived ligands. In doing so, key challenges and major advances in developing generic approaches for the elaboration of PPI inhibitors are highlighted. The challenges faced in developing such ligands as drug leads — and how criteria applied to these may differ from conventional small-molecule drugs — are summarized.

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Figure 1: α-Helix-mediated PPIs as targets for therapeutic intervention.
Figure 2: Small-molecule inhibitors of PPIs identified via high-throughput screening and fragment-based screening.
Figure 3: Different α-helix stabilization strategies.
Figure 4: Photocontrol of peptide conformational preference.
Figure 5: Foldamers as PPI inhibitors.
Figure 6: Original strategy for the design of type III mimetics.
Figure 7: Proteomimetic scaffolds with desirable features such as hydrophilic backbones (a–e), amenability to library assembly (f–l) and multifacial mimicry (m).

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Acknowledgements

The authors would like to acknowledge the financial support of the European Research Council (ERC-StG-240324) V.A. and A.J.W. Yorkshire Cancer Research (L348) K.L. and A.J.W. N.S.M. would like to acknowledge the University of Leeds for a Mary and Alice Smith Endowed Scholarship.

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Correspondence to Andrew J. Wilson.

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Azzarito, V., Long, K., Murphy, N. et al. Inhibition of α-helix-mediated protein–protein interactions using designed molecules. Nature Chem 5, 161–173 (2013). https://doi.org/10.1038/nchem.1568

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