Chemogenomic screening of the NLRP1 pathway

Inflammasomes are intracellular complexes that play a key role in innate immunity and inflammation. While NLRP1 was the first identified inflammasome, its activation mechanism and therapeutic potential have only recently come into focus. 

We investigated the pharmacology of NLRP1 by conducting a chemogenomic library screen (LOPAC©) using a cell reporter assay. We established a 384-well cellular screen using an A549-(NLRP1)-ASC-GFP reporter model (InvivoGen). NLRP1-specific induction of ASC-speck formation and pyroptotic cell death was confirmed using Val-boroPro (VbP). The LOPAC screening identified compounds that either fully or partially activate NLRP1-ASC-speck formation and cell death compared to VbP. We also identified inhibitors of VbP-induced NLRP1 activation. To ensure specificity, we conducted toxicity counter-screens using control NLRP1-null A549-ASC-GFP cells. 

In summary, we established a cellular screen for NLRP1 and unveiled compounds that can modulate NLRP1 activity. This approach provides valuable insights into the mechanisms and targets governing NLRP1 function. 

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