A Caspase-1-cathepsin AND-Gate Probe for Selective Imaging of Inflammasome Activation.

Caspase-1 is a key mediator of the inflammasome pathway, which is associated with several inflammatory disorders including obesity, diabetes mellitus, cardiovascular diseases, cancers, and chronic respiratory diseases. Although substrate-based probes can be used to visualize the activity of caspase-1, none are selective enough for use as imaging agents. Here, we report the design and synthesis of an AND-gate substrate probe (Cas1-Cat-Cy7) that requires processing by both caspase-1 and cathepsins to produce a signal. Because both enzymes are found together and active in tissue locations where cells are undergoing caspase-1-mediated pyroptosis, the resulting probe can be used to image sites of caspase-1-mediated inflammation. We demonstrate that the probe produces selective signals in ex vivo biochemical and cellular assays and in a mouse model of acute inflammation.