A common motif found at the interface of
PPIs is the α-helix. This provides a regular structure that can serve as a
template for small molecule and peptide development. Amongst others, the PPIs
of several oncoproteins are α-helix mediated, such as p53/hDM2 and NOXA-B/MCL-1.⁵ We aim to develop generic approaches to the discovery of effective α-helix mediated PPI
inhibitors using a combination of in
silico design, synthetic methodology and experimental validation.

Our
approaches to the development of small molecule inhibitors have been twofold:
computationally informed rational design to dissect key determinants of
protein-protein binding interactions, and the synthesis and screening of small
molecule libraries to identify selective small molecule inhibitors. Using a
predictive approach, coupled with synthesis, and subsequent determination of
the binding affinities of a library of variant peptides, we have developed
‘hot-spot’ models for several α-helix
mediated PPIs. We have then utilised these models to progress towards discovery
of selective small molecule inhibitors. This has deepened our understanding of
PPI topography, increased the robustness of our approach and will facilitate
the identification of low molecular weight PPI inhibitors.

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R. Arkin, Y. Tang and J. A. Wells, Chem. Biol., 2014, 21, 1102–1114.

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Clackson and J. A. Wells, Science., 1995, 267, 383–386.

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