Small-molecule inhibitor: MG132

Name

History: MG132 was a commercial product of Proscript (formerly Myogenics, Cambridge, MA). Early references to its use as an inhibitor of the peptidase activities of the proteasome include those of Lee & Goldberg (1996) and Yang et al. (1996).
Peptidases inhibited: Best known as an inhibitor of the proteasome, but is not a highly selective one. Very similar compounds are known to inhibit cathepsins (family C1) and calpains (family C2). Also inhibits gamma-secretase: Pinnix et al. (2001).
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Cardioprotective activity of MG132 has been suggested by Luss et al. (2002).

Inhibitor class: This is a compound of the aldehyde class. The discovery of leupeptin in the late 1960s drew attention to the potential of aldehydes as peptidase inhibitors, and the inhibition of papain by synthetic aldehydes was further studied by Wolfenden and co-workers (e.g. Westerik & Wolfenden, 1972). Many aldehydes are now known as inhibitors of serine, cysteine or threonine peptidases. They form hemiacetal or thiohemiacetal conjugates with the essential hydroxyl or thiol group of the enzyme that are transition state analogues (Bendall et al., 1977). The compounds exist predominantly in their hydrated forms in aqueous solution, but only the aldehyde is an effective inhibitor (Bendall et al., 1977). Peptide aldehydes and semicarbazones are valuable ligands for affinity chromatography of serine and cysteine peptidases (Rich et al., 1986; Dando & Barrett, 1992). Aldehydes can also act as inhibitors of metallopeptidases (Strater & Lipscomb, 1995).