Small-molecule inhibitor: CLIK148

Name

History: An early report on CLIK148 was that of Tsuge et al. (1999) describing the crystal structure of the complex with papain.
Peptidases inhibited: Papain and cathepsin L, at least, are inhibited. CLIK148 is described as 'cathepsin L-specific' (Tsuge et al., 1999).
Mechanism: Inactivation of the papain-like cysteine peptidase is by S-alkylation of the active site cysteine, as in the case of E64, but unlike most of the epoxide inhibitors of cysteine peptidases that have been described, CLIK148 binds in both S and S" subsites (Tsuge et al., 1999).
Pharmaceutical relevance: In vivo effects of CLIK148 on Thy-1 and Thy-2 immune responses and on bone resorption have been described (Zhang et al., 2001; Katunuma et al., 2002; Onishi et al., 2004).

Structure
Chemical/biochemical name: pyridylethylamido-N-(transcarbamoyloxirane-2-carbonyl)-L-phenylalanine-dimethylamide

Inhibitor class: This compound is of the epoxysuccinate class of inhibitors, which affect primarily cysteine peptidases in clan CA. The compounds inhibit irreversibly by S-alkylation of the catalytic cysteine, which results in opening of the epoxide ring. A thioester bond is formed by nucleophilic attack at C2 or C3 of the epoxide ring. Powers et al. (2002) (pp. 4664-4675) provide an authoritative review of epoxysuccinyl peptides as peptidase inhibitors.
Comment: Another epoxide that binds in both S and S" subsites is NS-134 (Stern et al., 2004).
Reviews: The CLIK-series of inhibitors specifically have been reviewed by Katunuma et al. (1999).