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首页> 外文期刊>Biochemistry >Highly potent irreversible inhibitors of neutrophil elastase generated by selection from a randomized DNA-valine phosphonate library.
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Highly potent irreversible inhibitors of neutrophil elastase generated by selection from a randomized DNA-valine phosphonate library.

机译：通过从随机的DNA-缬氨酸膦酸酯文库中选择而产生的中性粒细胞弹性蛋白酶的高效不可逆抑制剂。

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摘要

We incorporated a phosphonate irreversible inhibitor of neutrophil elastase into a randomized DNA library and, using the SELEX process, iteratively selected these assemblies for the most potent elastase inhibitors. The inhibitors were selected against purified elastase and against secreted elastase in the presence of activated neutrophils. Very active aptamer inhibitors were obtained by both methods, with second-order rate constants for inactivation of human neutrophil elastase ranging (1-3) x 10(8) M(-1) min(-1). These rates exceed those of any reported irreversible inhibitor of elastase and exceed the previous best phosphonate inhibitors by 80-fold. The selected inhibitors are also significantly more potent than alpha-1 proteinase inhibitor in blocking degradation of elastin by activated neutrophils. In contrast to a previous experiment [Smith et al. (1995) Chem. Biol. 2, 741-750], a single-enantiomer form of the valyl phosphonate was used rather than a racemic mixture. Our analysis shows that this use of a chirally resolved valyl phosphonate results in selection of much more potent inhibitors and that these inhibitors specifically potentiate a single enantiomeric form of the phosphonate.
机译：我们将中性粒细胞弹性蛋白酶的膦酸酯不可逆抑制剂整合到随机的DNA文库中，并使用SELEX流程，反复选择了最有效的弹性蛋白酶抑制剂的这些组装。在活化的中性粒细胞存在下，选择针对纯化的弹性蛋白酶和分泌的弹性蛋白酶的抑制剂。通过这两种方法均获得了非常活跃的适体抑制剂，用于灭活人类嗜中性粒细胞弹性蛋白酶的二级速率常数范围为（1-3）x 10（8）M（-1）min（-1）。这些比率超过任何报道的不可逆的弹性蛋白酶抑制剂，并且比以前最好的膦酸酯抑制剂高80倍。所选的抑制剂在阻止活化的中性粒细胞降解弹性蛋白方面也比α-1蛋白酶抑制剂有效得多。与先前的实验相反[Smith等。 （1995）Chem。生物学2，2，741-750]，使用单对映体形式的戊酸膦酸酯而不是外消旋混合物。我们的分析表明，手性拆分的戊基膦酸酯的这种使用可导致选择更有效的抑制剂，并且这些抑制剂可特异性地增强膦酸酯的单一对映体形式。

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