Optimisation of inhibitors of APP

本提案的目的是确定有效的、可溶的和细胞可渗透的化学工具作为APP的抑制剂，其具有进一步验证抑制机制和进一步开发成治疗药物的潜力。我们的策略是利用APP的高分辨率结构，在计算合理的命中验证练习，开发有效的和细胞渗透性抑制剂。其目标是产生可以进一步开发成治疗剂的铅样化学探针。该项目建立在利兹大学（UoL）的现有优势基础上，将小分子命中识别和验证策略以及肽酶生物化学和抗疟疾药物发现方面的专业知识与UoL和巴斯大学（UoB）的APP结构生物学专业知识相结合。有趣的是，APP最近也成为抗癌药物开发的目标。在项目过程中开发的抗疟疾药物的化学工具也将被探索，以重新用于抗癌治疗作为新型敏化剂的能力。我们与帝国理工学院的团队进行了良好的合作，以进一步发展这种方法。

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.