Novel peptide inhibitors for interleukin-1β processing in monocytes

Interleukinan inflammatory mediator released by human monocytes, is synthesized as a 269-mer precursor. It is cleaved by a cytoplasmic cysteine protease termed ILconverting enzyme (ICE) at to produce the active cytokine. ICE and its homologues, which are responsible for apoptosis, appear to belong to a new cysteine protease family. Effective ICE inhibitors are peptidyl aspartals (Asp-H) and (acyloxy)methanes [1]. A recent study reported [2] that (i) the analog of the latter having the homo-aspartyl (hAsp) residue, is inactive which indicatesthe key role of Asp CO in recognition; (ii) ICE accepts both Dand LAsp at the of both kinds of inhibitors. It is noted that epimerization occurs slowly at the -Asp and it is not known whether or not ICE catalyzes this process. The mechanism of the inhibition of cysteine proteases by peptidyl halomethanes and (acyloxy)methanes assumes the thiolate can react directly with the (a) as well as the adjacent halomethyl or (acyloxy)methyl group (b) [1]. In path b, one may expect that the thiolate (i) can contact the -proton of the temporarily bound and produce the LAsp-thiomethane product via proton abstraction and asymmetric induction, and (ii) can also attack the CO of hAsp that results in reversible inhibition; lack of such interaction with the -hAsp analog studied may be due to steric hindrance. Starting from these findings and speculations we compared the inhibiting activity of some peptide i-homoaldehydes to their parent -aldehydes against ICE, papain, trypsin and thrombin.