De novo discovery of bicyclic cysteine-rich peptides targeting gasdermin D

= 125 nM) and stabilized it against cleavage by caspase proteases. The bCRPs prevented the pore formation in liposome leakage assays and inhibited the secretion of IL-1β and lactate dehydrogenase from pyroptotic THP-1 cells. The potency, high metabolic stability, and synthetic accessibility of the discovered compounds make them promising leads for the development of GSDMD-targeting therapeutics.