Small-molecule inhibitor: DCI

Name

History: 3,4-Dichloroisocoumarin was described as a mechanism-based inactivator of serine peptidases by Harper et al., 1985.
Peptidases inhibited: All serine peptidases tested have been found to be inhibited, with the exception of complement factor C2 and complement factor B. Half-times (s) for inhibition at 1 millimolar inhibitor (Salvesen & Nagase, 2001) are: 3.5 (trypsin), 1.2 (chymotrypsin), 0.08 (neutrophil elastase), 25 (cathepsin G), 0.25 (glutamyl endopeptidase I). Also inhibited are the peptidase activities of the proteasome: Orlowski & Michaud, 1989) and various cysteine peptidases including papain.
Mechanism: Inhibition is irreversible (see Class).

Structure
Related inhibitors: Many analogues of DCI have been evaluated as peptidase inhibitors (Powers et al., 2002).

Inhibitor class: This compound is of the isocoumarin class. As is explained by Powers et al. (2002), isocoumarins are potent, irreversible inhibitors of serine peptidases. Many of them are mechanism-based inhibitors, and the inactivation occurs by opening of the isocoumarin ring by the active site serine residue to form an acyl enzyme that can be stable. Isocoumarins can also be 'suicide' inhibitors when a new reactive structure is unmasked during the acylation reaction, and this reactive species can further react with a nucleophile. Isocoumarins have limited stability in aqueous solution, especially in the presence of thiol compounds and other nucleophiles. Exact data are given by Powers et al. (2002).
Comment: DCI has become an important reagent for the identification of serine peptidases, and is generally much more reactive than PMSF with serine peptidases.
Reviews: Powers et al. (2002)