MECHANISM-BASED EVOLUTION OF NOVEL CATALYTIC ANTIBODIES

在发现抗体具有催化活性后， 过渡态类似物，很明显抗体可以催化 在自然界中催化的一系列化学反应 酵素。最近的工作集中在没有发生的化学反应上。 在自然系统中，例如Diels-Alder反应，然而，它可以 发生在化学上。催化抗体的优势在于它们可以 也催化因空间位阻而在化学上不利的反应 障碍物。建议对Desired的抗体催化作用进行研究。 反应，从对高度催化的剖析开始 不利于SYN消除反应生成顺式烯烃。第二 主要目的是通过利用免疫球蛋白诱导功能改善的抗体 基于机制的归纳法。我们将利用相当多的专业知识 以及在实验室进行半抗原设计和抗体生产的经验 和角色塑造。预计与中国的卓有成效的合作 其他三个项目将遵循以下概述的开始 建议书，不久将开始使用两种X射线进行结构工作 产生的几种催化抗体的结晶学和核磁共振 这是这个项目的一部分。这项工作将使我们更好地理解 抗体催化的结构基础，将给出有价值的 对溶液中催化性质的总体洞察。

Following the discoveries of catalytic activity in antibodies raised to transition state analogs, it has become clear that antibodies can catalyze a wide range of chemical reactions that are catalyzed in nature by enzymes. Recent work has focused on chemical reactions that do not occur in natural systems, such as Diels-Alder reactions, which, however, can occur chemically. Catalytic antibodies have the advantage that they can also catalyze reactions that are chemically disfavored due to steric hindrance. It is proposed to study antibody catalysis of disfavored reactions, beginning with the dissection of the catalysis of a highly disfavored syn elimination reaction to form a cis olefin. The second major aim is to elicit antibodies of improved function by utilizing mechanism-based induction. We will be utilizing considerable expertise and experience in the laboratory in hapten design and antibody production and characterization. It is anticipated that fruitful collaborations with the other three projects will follow the beginnings outlined in this proposal, and that structural work will commence shortly using both X-ray crystallography and NMR on several of the catalytic antibodies produced as part of this project. This work will lead to a better understanding of the structural basis of antibody catalysis, and it will give valuable insights into the nature of catalysis in solution in general.