A caspase-1-cathepsin AND-gate probe for selectiveimaging of inflammasome activation

Chen, S.; Goncin, U.; Zhu, J.; Su, S.-P.; Czyzyk, T. A.; Miller, C. O.; Kashfi Sadabad, R.; Bogyo, M.

doi:10.1101/2025.05.27.656501

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bioRxiv · 10.1101/2025.05.27.656501

A caspase-1-cathepsin AND-gate probe for selectiveimaging of inflammasome activation

Chen, S.·Goncin, U.·Zhu, J.·Su, S.-P.·Czyzyk, T. A.·Miller, C. O.·Kashfi Sadabad, R.·Bogyo, M.

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Abstract

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.

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Chen, S., Goncin, U., Zhu, J., Su, S.-P., Czyzyk, T. A., Miller, C. O., Kashfi Sadabad, R., Bogyo, M.. 2025-05-30. A caspase-1-cathepsin AND-gate probe for selectiveimaging of inflammasome activation. https://doi.org/10.1101/2025.05.27.656501

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