Lnterleukin-1β Converting Enzyme: Biology and the Chemistry of Inhibitors

Abstract

Interleukin-1β converting enzyme (ICE) catalyzes processing of biologically inactive pro IL-1β to mature II-1β. IL-1β is implicated in the pathogenesis of a number of inflammatory diseases, suggesting that compounds which inhibit ICE and reduce levels of the mature cytokine may have therapeutic utility. ICE and related homologs also appear to play a role in the pathway leading to apoptosis (programmed cell death), raising the possibility that inhibitors of ICE may be useful in/ ' diseases resulting from inappropriate regulation of apoptosis. ICE defines a new class of cysteine protease as confirmed through X-ray crystal structure determination of peptide inhibitor-ICE complexes. The enzyme exists as a (p20)2/(p10)2 tetramer and binds its peptide inhibitors via an extended P-sheet. A variety of strategies for the discovery of inhibitors of ICE have been successfully explored. Peptidyl aspartyl aldehydes and phenylalkyl ketones are potent reversible inhibitors of the enzyme, in analogy with the classic results obtained with other cysteine proteases. Selective irreversible inhibition of ICE is provided by compounds such as aspartyl diazomethyl ketones and aspartyl (arylacyloxy)methyl ketones, which appear to inactivate the enzyme through alkylation of the side chain thiol of Cys285. Several structurally distinct functional groups can replace the (arylacyl)oxy- moiety as a leaving group, including diphenylphosphinic acid and 5-hydroxy-1-phenyl 3- trifluoromethyl-pyrazole. Non-peptidic 3-chloropyridazines have also been described as irreversible inactivators of ICE.