Katz B A, Finer-Moore J, Mortezaei R, Rich D H, Stroud R M
Arris Pharmaceutical Corporation, South San Francisco, California 94080, USA.
Biochemistry. 1995 Jul 4;34(26):8264-80. doi: 10.1021/bi00026a008.
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 novel, potent (Ki approximately 7 nM), and more specific inhibitors of individual serine proteases, by derivitizations of compounds obtained by epitaxial selection.
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。在硼原子处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与胰蛋白酶样酶的紧密结合，并引入了可用于蛋白酶之间选择性的额外基团。通过一系列醇与抑制剂硼酸酯氧的反应形成，结构最兼容的醇衍生化抑制剂要么通过与酶结合（外延选择）来选择，要么通过在酶表面的外延反应来组装。衍生化硼酸酯的质谱分析和复合物的X射线晶体学确定了所产生抑制剂的化学结构和三维相互作用。通过对外延选择获得的化合物进行衍生化，该方案还设计出了新型、强效（Ki约为7 nM）且对单个丝氨酸蛋白酶更具特异性的抑制剂。
