Esterase Specificity for Pharmacology and Chemical Biology

药理学和化学生物学的酯酶特异性

• 批准号: 10017292
• 负责人: Ronald T Raines
• 金额: $ 24.92万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-09-20 至 2021-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10017292
• 关键词: Alcohols; BODIPY; Basic Science; Biological Assay; Biology; Cancerous; Cell membrane; Cells; Chemicals; Data; Disease; Enzymatic Biochemistry; Enzymes; Esters; Ethanol; Exposure to; Fluorescence; Future; Glutamates; Goals; Health; Healthcare; Human; Hydrolysis; Libraries; Location; Masks; Modernization; Mus; N-glycylglutamic acid; Patients; Peptides; Pharmaceutical Preparations; Pharmacology; Pharmacopoeias; Physiological; Prodrugs; Proteins; Research; Specificity; Substrate Specificity; Tissues; Variant; Work; base; cell type; chemotherapeutic agent; design; drug development; esterase; functional group; glutamyl endopeptidase; high throughput screening; human tissue; lysylglycine; novel; public health relevance; research and development; side effect; small molecule; technology development; tool

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.

项目概要/摘要 人体细胞中很少有分子含有酯。同样，人体细胞也具有高 酯酶活性。该活动通常被用来交付 作为前药的药物制剂，其中羧基部分被掩蔽为 酯类。前药中的酯通常是用乙醇制成的，乙醇无毒 作为酯水解的副产物。尽管酯酶在不同组织中存在差异 和细胞类型，酯酶特异性的变化在当前的研究中没有被利用 药典。本研究旨在为以下方面提供技术基础： 根据特定的情况定制前药（和潜在探针）的酒精部分 生理背景。工作将从开发高通量检测开始 用于酯酶催化的烷基酯水解，其中醇蛋白 酯是一个变量。然后，通过反应合成酯库 醇具有共同的中间体。最后，酯酶底物的概况 将在广泛的组织、细胞类型和血清中开发特异性。 内源性酯酶的底物特异性的随后概况 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能够将前药和潜在探针设计纳入 新境界。