Small-molecule inhibitor: Ac-Leu-Ala-Ala-Gln(Me2)-FMK

Name

History: Ac-Leu-Ala-Ala-Gln(Me2)-FMK was developed as an inhibitor of human hepatitis A virus picornain 3C by Morris et al. (1997).
Peptidases inhibited: This compound is known only as an inhibitor of hepatitis A virus picornain 3C. The Leu-Ala-Ala-Gln sequence of the peptide part of the inhibitor molecule tends to mimic the sequences of cleavage sites in the viral polyprotein.
Mechanism: The mode of binding to the enzyme was shown by a high-resolution crystal structure that suggests a mechanism of inactivation of picornains by methyl ketone inhibitors that is distinct from that of serine peptidases or of cysteine peptidases in family C1 by this class of compound (Yin et al., 2006).
Pharmaceutical relevance: Picornain 3C peptidases are drug targets for several viral diseases of humans and animals.

Structure
Chemical/biochemical name: N-acetyl-leucyl-alanyl-alanyl-(N,N-dimethyl)glutamine-fluoromethylketone

Inhibitor class: This compound is of the halomethylketone class of cysteine peptidase inhibitors. Both chloro- and fluoromethylketones inhibit cysteine peptidases, and the fluoromethylketones are generally specific for cysteine peptidases. These compounds are activated ketones that form tetrahedral adducts at the active site, and may go on to react covalently, forming thioethers with the active site cysteine. The halomethylketones have been reviewed by Powers et al. (2002), pp. 4646 - 4656, and Yin et al. (2006).