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.
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.
复制标题
肽基乙烯基砜：一类新型有效的选择性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。
作者：
Dieter Bro;J. Klaus;K. Okamoto;D. Rasnick;J. Palmer
肽基乙烯基砜是一类新型的高效、特异的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具有高度活性，对组织蛋白酶S的最高kinact/K1值超过10(7)M(-1) x S(-1)，对组织蛋白酶O2和l的最高kinact/K1值超过10(5)M(-1) x S（-1）。为了研究新型人类组织蛋白酶O2的主要特异性位点和这类新型抑制剂的有效性，合成了一系列具有P2残基变化的肽基乙烯基砜。P2位置的亮氨酸被证明是对组织蛋白酶O2最有效的残基，对组织蛋白酶S和l也是如此。组织蛋白酶O2和S对P2疏水非支链残基如氨基己酸（去甲亮氨酸）、蛋氨酸和氧化蛋氨酸的可及性都降低，但它们对P2位置的苯丙氨酸的亲和力不同。相比之下，组织蛋白酶S在其S2亚位上接受的疏水残基范围比组织蛋白酶O2和L更广。组织蛋白酶O2中主要特异性决定子位口袋S2在空间上似乎比组织蛋白酶S和L更受限制。
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.