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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.

机译:肽基乙烯基砜:一类新的有效和选择性的半胱氨酸蛋白酶抑制剂:与组织蛋白酶S和L相比,人组织蛋白酶O2的S2P2特异性。

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摘要

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 kinact/K1 values exceed 10(7)M(-1) x s(-1) for cathepsin S and 10(5)M(-1) x 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.
机译:肽基乙烯基砜是一类新型的强效和特异性半胱氨酸蛋白酶抑制剂。它们对治疗上重要的组织蛋白酶O2,S和L具有高活性。组织蛋白酶S和10(5)M(-1)xs的最高kinact / K1值超过10(7)M(-1)xs(-1)。 (-1)用于组织蛋白酶O2和L。为了研究新型人组织蛋白酶O2的主要特异性位点以及这种新型抑制剂的有效性,合成了一系列在P2残基上有所变化的肽基乙烯基砜。事实证明,P2位置的亮氨酸是组织蛋白酶O2和组织蛋白酶S和L的最有效残基。组织蛋白酶O2和S与P2疏水性非支链残基(如氨基己酸(正亮氨酸),甲硫氨酸和被氧化的)的可及性降低。甲硫氨酸,但在P2位置对苯丙氨酸的亲和力不同。相反,组织蛋白酶S在其S2亚位中比组织蛋白酶O2和L接受更广泛的疏水残基。组织蛋白酶O2中决定主要特异性的亚位点S2口袋似乎比组织蛋白酶S和L在空间上受到更大的限制。

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