Small-molecule inhibitor: Ada-Ahx3-L3VS

Name

History: Ada-Ahx3-L3VS was the most potent of the vinyl sulfone inhibitors of the proteasome described by Kessler et al., 2001.
Peptidases inhibited: Ada-Ahx3-L3VS is an inhibitor of the proteasome. It inhibits the pyroglutamyl peptidase, trypsin-like and chymotrypsin-like activities (T01.010, T01.011 and T01.012, respectively) to similar extents (Kessler et al., 2001).
Mechanism: Inhibition is irreversible, resulting from covalent modification of the catalytic threonine (Bogyo et al., 1997).

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.
Comment: Ada-Ahx3-L3VS is cell-permeant.
Reviews: Powers et al., 2002