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靶点，因为目前的方法无法在临床试验中转化。NLRP 3炎性体的活化升高与NAD酶SARM 1的活化偶联，已经涉及神经变性的早期步骤。同时抑制这两个靶点看起来是减轻神经炎症的有希望的策略。该项目将产生DUNeS：NLRP 3和SARM 1的原型双特异性抑制剂，利用最近的结构生物学发现。将使用正交试验级联设计、合成和测试化合物，包括计算、生物物理、基于细胞和表型的试验。一旦得到验证，化合物将为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