ANTIBODIES AS CATALYSTS

抗体作为催化剂

• 批准号: 3294526
• 负责人: DONALD M HILVERT
• 金额: $ 20.65万
• 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 1995-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/3294526
• 关键词: Diels Alder reaction; X ray crystallography; analog; biological products; carboxylate; carboxylation; catalyst; chemical addition; chemical bond; chemical kinetics; enzyme inhibitors; enzyme linked immunosorbent assay; enzyme mechanism; haptens; hybrid antibody; hybridomas; hydrogen bond; immunoglobulin structure; isoxazoles; laboratory mouse; molecular cloning; molecular rearrangement; monoclonal antibody; nucleic acid sequence; protein engineering; protein structure function; saturated /unsaturated bonds; stereochemistry

Our program aims to develop and exploit general strategies for preparing enzyme-like catalysts with tailored activities and specificities. Recent attention has focused on the mammalian immune system as a source of such molecules. Using the transition state analog approach enunciated by Jencks in 1969, we and others have generated antibody proteins that catalyze a wide variety of chemical transformations, including ester and amide hydrolysis, photochemical processes, a sigmatropic rearrangement, a elimination, and a Diels-Alder cycloaddition. In this proposal we seek to expand our program in this area and have specifically targeted catalysis of concerted chemical transformations, especially pericyclic processes and decarboxylations. These reactions do not require participation of active-site nucleophiles, general acids or general bases, but should be highly sensitive to strain and entropy considerations. The latter factors distinguish enzymes from ordinary chemical catalysts and are the principal effects that antibodies are likely to exploit in doing chemical work. Preparation and study of immunoglobulins that accelerate these processes efficiently will enhance our understanding of how natural enzymes achieve enormous rate enhancements and exacting selectivities. Further, pericyclic reactions are among the most important and versatile transformations available to synthetic chemists for constructing carbon-carbon bonds in complex natural products, therapeutic agents and synthetic materials of all kinds. The ability to catalyze these processes with the high rates and selectivities of enzymes will therefore have important consequences for practical applications of this technology in organic synthesis. The design of enzyme-like catalysts with tailored specificities also has far-reaching implications for medical research and the development of therapies related to cancer and other diseases. Within the foreseeable future, antibody catalysts may well be used as drugs that operate in vivo through catalysis to alter tumor metabolism or to destroy carcinogens and other toxins.

我们的计划旨在制定和利用一般策略来准备 具有量身定制的活动和特异性的酶样催化剂。 最近的 注意力集中在哺乳动物的免疫系统上 分子。 使用Jencks阐明的过渡状态模拟方法 1969年，我们和其他人产生了催化A的抗体蛋白 各种化学转化，包括酯和酰胺 水解，光化学过程，sigmatropic重排，一个 消除和Diels-alder Cyclotition。 在这个建议中，我们寻求 扩大我们在该领域的计划，并专门针对 一致的化学转化，尤其是周环过程和 脱羧。 这些反应不需要参与 活性位点接亲核者，一般酸或一般碱，但应为 对应变和熵考虑高度敏感。 后一个因素 区分酶和普通化学催化剂，是主要的 抗体可能利用化学作用时可能利用的影响。 加速这些过程的免疫球蛋白的制备和研究 有效地将增强我们对天然酶如何实现的理解 巨大的增强率和精确的选择性。 此外，周期性 反应是最重要，通用的转换之一 可用于合成化学家，用于构建碳碳键 所有的复杂天然产品，治疗剂和所有的合成材料 种类。 以高率和高率催化这些过程的能力和 因此，酶的选择性将对 该技术在有机合成中的实际应用。 设计 具有量身定义特异性的酶状催化剂的催化剂也有深远的角度 对医学研究的影响和与疗法相关的发展 癌症和其他疾病。 在可预见的将来，抗体 催化剂很可能被用作通过催化在体内操作的药物 改变肿瘤代谢或破坏致癌物和其他毒素。