EPISELECTION - NOVEL K-I-SIMILAR-TO NANOMOLAR INHIBITORS OF SERINE PROTEASES SELECTED BY BINDING OR CHEMISTRY ON AN ENZYME SURFACE
EPISELECTION - NOVEL K-I-SIMILAR-TO NANOMOLAR INHIBITORS OF SERINE PROTEASES SELECTED BY BINDING OR CHEMISTRY ON AN ENZYME SURFACE
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DOI：
10.1021/bi00026a008
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发表时间：
1995-07-04
期刊：
影响因子：
2.9
通讯作者：
STROUD, RM
中科院分区：
文献类型：
--
作者：
KATZ, BA;FINERMOORE, J;STROUD, RM
利用外延选择开发了一类新型的基于机制的丝氨酸蛋白酶抑制剂。在硼上被一种或多种醇酯化的三肽硼酸酯保留了与过渡态类似物相关的胰蛋白酶样酶的紧密结合，并掺入了可用于蛋白酶之间选择性的附加基团。由一系列醇与抑制剂硼酸氧反应形成，结构上最相容的醇衍生抑制剂要么通过与酶结合来选择（外延选择），要么通过酶表面的外延反应进行组装。衍生硼酸盐的质谱分析和复合物的 X 射线晶体学鉴定了化学结构和所产生的抑制剂的三维相互作用。该方案还通过外延选择获得的化合物的衍生化，设计了单个丝氨酸蛋白酶的有效（K-i 类似于 7 nM）和更特异的抑制剂。
A novel class of mechanism-based inhibitors of the serine proteases is developed using epitaxial selection. Tripeptide boronates esterified by an alcohol or alcohols at the boron retain the tight binding to trypsin-like enzymes associated with transition-state analogs and incorporate additional groups that can be utilized for selectivity between proteases. Formed by reaction of a series of alcohols with the inhibitor boronate oxygen(s), the most structurally compatible alcohol-derivatized inhibitors are either selected by binding to the enzyme (epitaxial selection) or assembled by epitaxial reaction on the enzyme surface. Mass spectrometry of the derivatized boronates and X-ray crystallography of the complexes identify the chemical structures and the three-dimensional interactions of inhibitors generated. This scheme also engineers navel, potent (K-i similar to 7 nM), and more specific inhibitors of individual serine proteases, by derivitizations of compounds obtained by epitaxial selection.