ANTIBODIES AS CATALYSTS

抗体作为催化剂

• 批准号: 2770945
• 负责人: ROBYN L STANFIELD
• 金额: $ 34.19万
• 依托单位: SCRIPPS RESEARCH INSTITUTE, THE
• 依托单位国家: 美国
• 财政年份: 1987
• 资助国家: 美国
• 起止时间: 1987-04-01 至 2000-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/2770945
• 关键词: Diels Alder reaction; abzyme; carboxylation; catalyst; chemical addition; chemical elimination; chemical kinetics; chemical models; drug design /synthesis /production; enzyme mechanism; hybrid antibody; laboratory mouse; laboratory rabbit; molecular rearrangement; monoclonal antibody; phosphomonoesterases; protein engineering; protein structure function; vitamin B6

This is a proposal for renewal of our grant supporting work on imitating and understanding enzymic catalysis through the study of catalytic antibodies. Catalytic antibody technology represents one of the most versatile strategies for creating new enzymes to emerge in the last several years: antibodies raised against transition state analogs have catalyzed more than 50 chemical transformations with significant rate accelerations and high selectivity. The immediate challenge in this field is to generate catalysts with even greater chemical efficiency. The specific aims of this proposal address this issue in three ways. First, the structure and mechanism of four representative antibody catalysts will be investigated in detail. These agents catalyze a Claisen rearrangement, a bimolecular Diels-Alder cycloaddition, a medium-sensitive decarboxylation, and a base-dependent elimination reaction, respectively. Their study will contribute to our understanding of the basic principles of catalysis, including the roles of transition state complementarity, proximity effects, desolvation, and chemical catalysis, providing information relevant to the creation of more active catalysts. Second, by refining transition state analog design and by developing and implementing more effective screening technologies we hope to optimize the strategies that have been developed to generate individual catalytic antibodies. Third, genetic selection will be investigated as a tool for augmenting the activity of first-generation catalytic antibodies. By characterizing the genetic changes that accumulate as the antibody becomes more active we may gain fundamental insight into the evolution of molecular function. We anticipate that the lessons learned in this project will lead to the elaboration of general strategies for designing highly active artificial enzymes of wide applicability in chemistry, biology, and medicine. Specifically, we hope to create practical antibody catalysts for the synthesis of vitamin B6 and for the hydrolysis of phosphate monoesters.

这是一份关于延长我们资助仿制工作的拨款的建议 通过对催化作用的研究了解酶催化作用 抗体。催化抗体技术代表了最具代表性的 多才多艺的策略创造新的酶出现在最后 几年来：针对过渡状态类似物产生的抗体 催化了50多个化学转化，反应速度显著 加速和高选择性。这一领域面临的紧迫挑战 就是生产出化学效率更高的催化剂。这个 这项提案的具体目标通过三种方式处理这一问题。第一, 四种具有代表性的抗体催化剂的结构和作用机理 被详细调查。这些试剂催化克莱森重排， 中等灵敏的双分子Diels-Alder环加成反应 脱羧基和碱基依赖的消除反应。 他们的研究将有助于我们理解基本原则 催化作用，包括过渡态互补的作用， 邻近效应、去溶和化学催化，提供 与创造更具活性的催化剂有关的信息。第二，由 改进过渡状态模拟设计，并通过开发和实施 更有效的筛查技术我们希望优化策略 它们已经被开发出来以产生单独的催化抗体。 第三，将研究遗传选择作为一种工具来增加 第一代催化抗体的活性。通过将 随着抗体变得更活跃而积累的基因变化，我们可能 对分子功能的进化有基本的了解。我们 预计在该项目中学到的经验教训将导致 阐述设计高活性人工关节的一般策略 在化学、生物和医学中具有广泛适用性的酶。 具体地说，我们希望创造出实用的抗体催化剂 维生素B6的合成和磷酸单酯的水解。