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

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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