E-64 [L-trans-epoxysuccinyl-leucyl-amido(4-guanidino)butane] and related epoxides as inhibitors of cysteine proteinases.
1. E-64 [L-trans-epoxysuccinyl-leucyl-amido(4-guanidino)butane] was found to be an active site directed irreversible inhibitor of all of the cysteine proteinases tested except clostripain, and not to affect other enzymes. Thus it seems to be a powerful selective inhibitor for cysteine proteinases in mammalian systems. 2. The very high rate of inactivation of some cysteine proteinases, including cathepsins B and L, allows the molarity of active enzyme to be determined by stoichiometric titration with E-64. This incidentally calibrates the rate assay of the enzyme in terms of molar concentrations. 3. Measurement of rates of reaction of E-64 and a number of optically active analogues with cathepsins B, H and L has given some insight into structure-activity relationships. Cathepsin H is far less reactive than the other enzymes, and generally cathepsins B and L have reactivities rather similar to each other with the epoxide inhibitors.
D001665:Binding Sites; D001667:Binding, Competitive; D002401:Cathepsin B; D056655:Cathepsin H; D056668:Cathepsin L; D002403:Cathepsins / Q000037:antagonists & inhibitors; D003546:Cysteine Endopeptidases; D010450:Endopeptidases; D004852:Epoxy Compounds / Q000494:pharmacology*; D004988:Ethers, Cyclic / Q000494:pharmacology*; D007930:Leucine / Q000031:analogs & derivatives* / Q000494:pharmacology; D008968:Molecular Conformation; D011480:Protease Inhibitors; D013329:Structure-Activity Relationship
D004852:Epoxy Compounds; D004988:Ethers, Cyclic; D011480:Protease Inhibitors; D002403:Cathepsins; D010450:Endopeptidases; D003546:Cysteine Endopeptidases; D002401:Cathepsin B; D056668:Cathepsin L; D056655:Cathepsin H; D007930:Leucine; C024974:E 64