Small-molecule inhibitor: Z-Leu-Leu-Nle-H

Name

Peptidases inhibited: Z-Leu-Leu-Nle-H is commonly treated as a selective inhibitor of the aspartic peptidase presenilin 1 in the gamma-secretase complex, but it almost certainly inhibits other peptidases also. These are likely to include the threonine peptidase activities of the proteasome complex and cysteine peptidases such as the cathepsins (family C1) and calpains (family C2).

CID at PubChem: 16760646
Structure
Chemical/biochemical name: benzyloxycarbonyl-leucyl-leucyl-norleucinal
Formula weight: 476
Related inhibitors: This is a tripeptide aldehyde chemically very similar to Z-Leu-Leu-Leu-H, MG132.

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).