Small-molecule inhibitor: Nip-Leu-Leu-LeuVS-Me

Name

History: Nip-Leu-Leu-LeuVS-Me was amongst the first vinyl sulfone inhbitors of the proteasome to be described (Bogyo et al., 1997).
Peptidases inhibited: Nip-Leu-Leu-LeuVS-Me inhibits the pyroglutamyl peptidase, trypsin-like and chymotrypsin-like activities of the eukaryotic proteasome (T01.010, T01.011 and T01.012, respectively), but with preference for the chymotrypsin-like activity: Bogyo et al. (1997). The bacterial proteasome is also inhibited (McCormack et al., 1997), as is the bacterial HslUV peptidase: Sousa et al., 2002).
Mechanism: Inhibition is irreversible, resulting from covalent modification of the catalytic threonine (Bogyo et al., 1997). The crystal structure of the complex with the bacterial HslUV peptidase has been described (Sousa et al., 2002).

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: Nip-Leu-Leu-LeuVS-Me is a cell-permeant compound analogous to Z-Leu-Leu-LeuVS, and can be radio-iodinated (Schmidtke et al., 1999). The analogous compound, Nip-Leu-Leu-AsnVS-Me, in which one of the leucine sidechains is replaced by that of asparagine, reacts more equally with each of the components of the eukaryotic proteasome (Nazif & Bogyo, 2001).
Reviews: Powers et al., 2002