Small-molecule inhibitor: MDL28170

Name

History: Reported as an inhibitor of calpain, presumably calpain-1 and calpain-2, by Mehdi et al. (1988).
Peptidases inhibited: In addition to inhibition of calpains, inhibits adenain at 1x10^-6 M concentration (Cotten & Weber, 1995) and the gamma-secretase and zeta-secretase cleavages of Alzheimer"s precursor protein (Citron et al., 1996; Dong et al., 2005). MEROPS is not aware of rigorous tests of the specificity of this inhibitor, and notes that related hydrophobic peptide aldehydes (e.g. ALLN, ALLM) inhibit the proteasome: Orlowski et al., 1993), and cathepsins might well also be susceptible.
Mechanism: Inhibition is reversible.
Pharmaceutical relevance: Investigated as a therapeutic agent for the treatment of ischemic stroke and head and spinal trauma (Arataki et al., 2005).

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).
Comment: This small, hydrophobic molecule penetrates cell membranes (Lampi et al., 1992; Urthaler et al., 1997).