Small-molecule inhibitor: Z-Ile-Glu(OtBu)-Ala-Leu-H

Name

History: The synthesis and inhibitory activity of Z-Ile-Glu(OtBu)-Ala-Leu-H were described by Wilk & Figueiredo-Pereira (1993).
Peptidases inhibited: The chymotrypsin-like activity of the proteasome is potently inhibited, whereas there is no significant effect on the pyroglutamyl-peptide hydrolysing or trypsin-like activities that are due to catalytic subunits 1 and 2 respectively.
Mechanism: Inhibition is reversible. K_i for the chymotrypsin-like activity of the proteasome is 0.25 micro-M.
Pharmaceutical relevance: Aldehydes are rapidly metabolised in vivo, and so are not attractive drug candidates, but Z-Ile-Glu(OtBu)-Ala-Leu-H has been used in many experimental studies of the functions of the proteasome.

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).