Selective Activity‐Based Probes for Cysteine Cathepsins

By “reverse design”: The core structures of protease inhibitors, whose selectivity has been optimized by extensive medicinal chemistry, have been redesigned into selective protease substrates by replacing the reactive electrophilic group (e.g. nitrile) with a cleavable peptide bond. Attachment of appropriate reporter groups yields cell-permeable activity-based probes for the cellular imaging of selected cysteine cathepsins.