Peptidyl vinyl sulphones: A new class of potent and selective cysteine protease inhibitors: S₂P₂ specificity of human cathepsin 02 in comparison with cathepsins S and L

Peptidyl vinyl sulphones are a novel class of extremely potent and specific cysteine protease inhibitors. They are highly active against the therapeutically important cathepsins O2, S and L. The highest k_inact/K_i values exceed 10⁷ M^-1·s^-1 for cathepsin S and 10⁵ 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 class of inhibitors, a series of peptidyl vinyl sulphones with variations in the P₂ residue was synthesized. Leucine in the P₂ 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 accessibility towards P₂ hydrophobic non-branched residues such as aminohexanoic acid (norleucine), methionine and oxidized methionine, but are distinguished by their different affinity towards phenylalanine in the P₂ position. In contrast, cathepsin S accepts a broader range of hydrophobic residues in its S₂ subsite than cathepsins O2 and L. The primary specificity-determining subsite pocket S₂ in cathepsin O2 appears to be spatially more restricted than those of cathepsins S and L.