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 (DM), cardiovascular diseases (CVDs), 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 a AND-gate substrate probe (Cas1-Cat-Cy7) that requires processing by both caspase-1 and cathepsins to produce a signal. Because both enzymes are only found together and active at the site of inflammasome activation, the resulting probe can be used to image 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.