Optimisation of inhibitors of APP

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The objective of this proposal will be to identify potent, soluble and cell permeable chemical tools as inhibitors of APP with potential to further validate the mechanism of inhibition and for further development into a therapeutic drug. Our strategy is to exploit the high-resolution structure of APP in a computational rational hit validation exercise to develop potent and cell permeable inhibitors. The aim will be to generate lead-like chemical probes that can be further developed into therapeutic agents. The project builds on existing strengths at the University of Leeds (UoL), combining expertise in small molecule hit identification and validation strategies and peptidase biochemistry and anti-malarial drug discovery with expertise in APP structural biology at UoL and University of Bath (UoB). Fascinatingly, APP has also recently emerged as a target for development of anti-cancer agents. Chemical tools developed as anti-malerial agents during the course of the project will also be explored for their ability to be re-purposed for anti-cancer therapy as novel sensitising agents. We have excellent collaborations with groups at Imperial College to further develop this approach.