DUNeS: Structure based development of dual specificity inhibitors of NLRP3 and SARM1

神经退行性疾病的治疗需要新的目标，因为目前的方法无法在临床试验中转化为药物。NLRP3炎症体的激活升高与NADase Sarm1的激活相结合，被认为与神经退变的早期步骤有关。同时抑制这两个靶点看起来是一个很有希望的减轻神经炎症的策略。该项目将利用最近的结构生物学发现，产生沙丘：NLRP3和Sarm1的典型双特异性抑制剂。化合物的设计、合成和测试将使用包括计算分析、生物物理分析、细胞分析和表型分析在内的正交级联分析。一旦得到验证，化合物将为一种新的治疗方式提供强有力的概念验证

Treatment of neurodegenerative disease needs new targets, as current approaches fail to translate in clinical trials. Elevated activation of the NLRP3 inflammasome coupled with activation of the NADase SARM1, have been implicated in early steps of neurodegeneration. Simultaneous inhibition of those two targets looks like a promising strategy to mitigate neuroinflammation. This project will generate DUNeS: prototypical dual specificity inhibitors of NLRP3 and SARM1, capitalising on recent structural biology discoveries. Compounds will be designed, synthesised and tested using orthogonal assay cascade, including computational, biophysical, cell-based and phenotypic assays. Once validated, compounds will provide a robust proof-of-concept for a novel therapeutic modality