Esterase Specificity for Pharmacology and Chemical Biology

项目摘要/摘要 人类细胞中几乎没有分子含有酯。同样，人类细胞也有很高的 酯酶活性。这一活动经常被利用来交付 作为前体药物的药理药物，其中的羧基部分被掩盖为 酯类化合物。前药中的酯通常是用无毒的乙醇制成的 作为酯水解的副产品。尽管不同组织中的酯酶不同 和细胞类型，酯酶特异性的变异在目前还没有被利用 药典。拟议的研究旨在为以下方面提供技术基础 将前药(和潜伏探针)的酒精部分定制为特定的 生理环境。工作将从开发一种高通量分析开始 用于酯酶催化的烷基酯的水解，其中醇蛋白 酯是一个变量。然后，通过反应合成一个酯库 带有共同中间体的醇。最后，给出了酯酶底物的分布 特异性将在广泛的组织、细胞类型和血清中发展。 内源酯酶底物专一性的后续研究 与药物开发和化学基础研究最相关的背景 生物学将使未来的努力将前药和潜在探针设计带入 新领域。

PROJECT SUMMARY/ABSTRACT Few molecules in human cells contain esters. Likewise, human cells have high esterase activity. That activity is exploited routinely for the delivery of pharmacological agents as prodrugs in which carboxyl moieties are masked as esters. The esters in prodrugs are typically made with ethanol, which is not toxic as a byproduct of ester hydrolysis. Although esterases vary in different tissues and cell types, variations in esterase specificity are not exploited in the current pharmacopeia. The proposed research seeks to provide the technological basis for tailoring the alcohol portion of prodrugs (and latent probes) to particular physiological contexts. Work will begin by developing a high-throughput assay for the esterase-catalyzed hydrolysis of alkyl esters in which the alcohol protein of the ester is a variable. Then, a library of esters will be synthesized by reacting alcohols with a common intermediate. Finally, a profile of esterase substrate specificity will be developed across a wide range of tissues, cell types, and sera. The ensuing profile of the substrate specificity of esterases endogenous in contexts most relevant for both drug development and basic research in chemical biology will enable future efforts to take prodrug and latent probe design into a new realm.