Small-molecule inhibitor: Z-Leu-Leu-Leu-vinylsulfone

Name

History: Z-Leu-Leu-LeuVS was amongst the first vinyl sulfone inhbitors of the proteasome to be described (Bogyo et al., 1997).
Peptidases inhibited: Z-Leu-Leu-Leu-VS inhibits the eukaryotic proteasome. The pyroglutamyl peptidase, trypsin-like and chymotrypsin-like activities (T01.010, T01.011 and T01.012, respectively) are all affected, but with preference for the chymotrypsin-like activity: Bogyo et al., 1997). The bacterial proteasome is also inhibited (McCormack et al., 1997).
Mechanism: Inhibition is irreversible.

Inhibitor class: This compound belongs to the class of Michael acceptor inhibitors. These are irreversible inhibitors specific for cysteine and threonine peptidases. The class includes vinyl sulfones and alpha, beta-unsaturated derivatives of amino acids and peptides. These inhibitors act by forming covalent bonds to the active site thiol of a cysteine peptidase. They have negligible reactivity with small-molecule thiol compounds and serine peptidases. The reaction proceeds via a Michael addition, with an attack on the beta-carbon of the inhibitor by the active site cysteine residue, followed by protonation of the alpha-carbon to form the thioether derivative. Reviewed by Powers et al. (2002), pp. 4683 - 4694.
Reviews: Powers et al., 2002