Small-molecule inhibitor: leupeptin

Name

Common name: leupeptin
Other names: Ac-Leu-Leu-Arg-H; N-acetyl-L-leucyl-L-leucyl-D,L-argininaldehyde; Gabadur; Neurodur

History: Leupeptin was discovered in the Umezawa group, in 1969 (e.g. Aoyagi et al., 1969).
Peptidases inhibited: Leupeptin inhibits a wide range of serine (families S1, S8), cysteine (families C1, C11) and threonine (family T1) peptidases. Apart from numerous peptidases in families S1 and C1, leupeptin is a potent inhibitor of clostripain: Kembhavi et al., 1991) and PACE4: Mains et al., 1997) and the trypsin-like activity of the proteasome: Savory & Rivett, 1993).
Mechanism: Leupeptin is a slow, tight-binding, transition state analogue inhibitor of cathepsin B (Schultz et al., 1989; Baici & Gyger-Marazzi, 1982). Crystal structures are available for complexes with trypsin: Kurinov & Harrison, 1996), papain: Schröder et al., 1993) and calpain 2: Moldoveanu et al., 2004).

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).