Inhibition of Protein-protein Interactions Using Designed Molecules
Conference Recording Jul 08, 2013
About the SpeakerFollowing a PhD at Warwick with Prof David Leigh and postdocs with Prof Andy Hamilton (Yale) and Prof E. (Bert) W. Meijer (Eindhoven), Andy Wilson joined the University of Leeds in 2004 where he has been since. Andy is the co-director of PPI-Net and Deputy Director of the Astbury Centre for Structural Molecular Biology at The University of Leeds. Andy’s research centres on using synthetic molecules to understand and control molecular recognition and self-assembly. The groups’ major current focus is on the development of inhibitors of protein-protein interactions.
Protein-protein interactions (PPIs) play a pivotal role in diseased states and so there is a pressing need for synthetic agents that selectively target these interfaces. What is not clear is how to do this using a small molecule, given that it must cover 800-1100Å2 of a protein surface and complement the discontinuous projection of hydrophobic and charged domains over a flat or moderately convex surface. Several general approaches tailored to particular protein topologies are emerging for the design of scaffolds that inhibit PPIs including: ‘proteomimetics’ and ‘surface mimetics’. Proteomimetics replicate the spatial projection of key binding residues from a secondary structural motif important in the target protein-protein interaction whilst surface mimetics present recognition domains from a core scaffold in a multivalent manner to achieve high affinity protein surface recognition. This presentation will outline our work in both areas. The development of solid-phase syntheses of aromatic oligoamides amenable to library generation will be described alongside preliminary screening results that illustrate such compounds act as inhibitors of the a-helix mediated PPIs. The design and synthesis of highly functionalised ruthenium tris(bipyridine) complexes that act as tuneable nM affinity receptors for proteins such as cytochrome c will also be described.
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