Inhibition of Protein-protein Interactions Using Designed Molecules

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April 29, 2013

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  • 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.

    Drug DiscoveryMicrofluidicsProteomics and Metabolomics

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