Small-molecule inhibitor: K777

Name

Peptidases inhibited: Inhibits cruzipain, cathepsin B and cathepsin L (Jacobsen et al., 2000). Also inhibited are histolysain (Melendez-Lopez et al., 2007), a cysteine peptidase of Schistosoma mansoni (Abdulla et al., 2007) and GsCL1 peptidase (Kongkerd et al., 2008).
Pharmaceutical relevance: K11777 has been reported to be in late-stage preclinical development for treatment of Chagas disease (Doyle et al., 2007) and also to show promise for schistosomiasis (Abdulla, 2007).

Structure
Chemical/biochemical name: N-methyl-piperazine-Phe-homoPhe-vinylsulfone-phenyl

Inhibitor class: This compound belongs to the class of Michael acceptor inhibitors. These are irreversible inhibitors specific for cysteine and threonine peptidases. The class includes vinyl sulfones and alpha, beta-unsaturated derivatives of amino acids and peptides. These inhibitors act by forming covalent bonds to the active site thiol of a cysteine peptidase. They have negligible reactivity with small-molecule thiol compounds and serine peptidases. The reaction proceeds via a Michael addition, with an attack on the beta-carbon of the inhibitor by the active site cysteine residue, followed by protonation of the alpha-carbon to form the thioether derivative. Reviewed by Powers et al. (2002), pp. 4683 - 4694.