PEPTIDYL VINYL SULFONES - A NEW CLASS OF POTENT AND SELECTIVE CYSTEINE PROTEASE INHIBITORS - S2P2 SPECIFICITY OF HUMAN CATHEPSIN-O2 IN COMPARISON WITH CATHEPSIN-S AND CATHEPSIN-L

Peptidyl vinyl sulphones are a novel class of extremely potent and spe cific cysteine protease inhibitors. They are highly active against the therapeutically important cathepsins O2, S and L. The highest k(inact )/K-i values exceed 10(7) M(-1). s(-1) for cathepsin S and 10(5)M(-1). s(-1) for cathepsins O2 and L. To study the primary specificity site of the novel human cathepsin O2 and the effectiveness of this novel cl ass of inhibitors, a series of peptidyl vinyl sulphones with variation s in the P-2 residue was synthesized. Leucine in the P-2 position was proven to be the most effective residue for cathepsin O2 and also for cathepsins S and L. Cathepsins O2 and S share a decreased accessibilit y towards P-2 hydrophobic non-branched residues such as aminohexanoic acid (norleucine), methionine and oxidized methionine, but are disting uished by their different affinity towards phenylalanine in the P-2 po sition. In contrast, cathepsin S accepts a broader range of hydrophobi c residues in its S-2 subsite than cathepsins O2 and L. The primary sp ecificity-determining subsite pocket S-2 in cathepsin O2 appears to be spatially more restricted than those of cathepsins S and L.