Epoxysuccinyl dipeptides as selective inhibitors of cathepsin B

Abstract

Epoxysuccinyl dipeptide analogs of E-64 (R-EpsLeuPro-R') (Figure 1) have been synthesized with the carboxylate group on the epoxide ring either free (R = OH) or converted to an ester or an amide (R = EtO or i-BuNH) and with the C-terminal amino acid proline either blocked (R' = OBzl) or free (R' = OH). These compounds were used to investigate the recently reported selectivity of this type of inhibitor for the lysosomal cysteine protease cathepsin B. It was shown that derivatization of the carboxylate on the epoxide ring confers selectivity for cathepsin B over papain only when it is combined to a dipeptidyl moiety with a free negatively charged C-terminal residue. It is proposed that this selectivity reflects interactions with histidine residues on a loop located in the primed subsites of cathepsin B which provides a positively charged anchor for the C-terminal carboxylate group of the inhibitor. The primed subsite loop of cathepsin B is not found in other cysteine proteases of the papain family and offers a unique template for designing selectivity in cysteine protease inhibitors.

An improved synthesis of aziridine-2,3-dicarboxylates via azido alcohols—epimerization studies

“…[1][2][3] Since these proteases play essential roles in various pathological processes, low molecular weight inhibitors could be useful therapeutic agents. One class of inhibitors comprises of peptides containing an epoxide [4][5][6][7][8][9][10][11][12][13] or aziridine [14][15][16][17][18][19] ring. 20 These three-membered heterocycles act as electrophilic head groups which can be attacked by the cysteine residue of the enzyme's active site thus leading to irreversible enzyme alkylation and inactivation.…”

Peptidyl vinyl sulphones: a new class of potent and selective cysteine protease inhibitors: S2P2 specificity of human cathepsin O2 in comparison with cathepsins S and L

“…Exceptions are peptidyl epoxides [8,9], peptidyl nitriles [10] and N-peptidyl-O-acylhydroxylamines [11]. Liu and Hanzlik [12] recently described Michael acceptors as a class of potential protease inhibitors.…”

Delineating functionally important regions and residues in the cathepsin B propeptide for inhibitory activity

“…Some success has been obtained using E-64 analogs developed for the specific inhibition of cathepsin B [10]. In this case selectivity is achieved through interaction with the 'occluding loop' of cathepsin B, a structural feature particular to this enzyme [11,12]. Selective inhibition of cathepsin B has also been observed with a 56 amino acid peptide derived from the proregion of the enzyme [13].…”