Antibodies as Catalysts

抗体作为催化剂

• 批准号: 6635953
• 负责人: IAN A WILSON
• 金额: $ 41.67万
• 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 2005-04-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/6635953
• 关键词: Diels Alder reaction; Drosophilidae; X ray crystallography; abzyme; biochemical evolution; biomimetics; biotechnology; biotherapeutic agent; biotransformation; chemical models; cholinesterases; cocaine; computer simulation; crystallization; drug abuse chemotherapy; drug metabolism; enzyme mechanism; human tissue; hybrid antibody; laboratory mouse; molecular dynamics; monoclonal antibody; protein engineering; protein structure function; structural biology; technology /technique development

DESCRIPTION (provided by applicant): Structural insights into antibody catalysis are critical for novel design and improvement of effective biocatalysts. Thus, a major goal in this renewal is to focus on catalytic antibodies that will have either a direct impact on public health issues, be of general chemical and biotechnological utility, or will provide mechanistic guidelines for enhancement of catalytic efficiency or specificity. Structural, biochemical, chemical, and theoretical approaches will be combined in order to provide directions for new ligand design or mutagenesis. The antibodies under study catalyze pericyclic, elimination, transfer and esterase reactions. General principles derived from these abzyme crystal structures will be specifically applied to enhance the cocaine binding and degrading activities of humanized antibodies and human enzymes. Cocaine-degrading antibodies have tremendous therapeutic potential in immunotherapy for cocaine addiction, thereby reducing the social and economic burden caused by this drug. The individual specific aims are to determine x-ray crystal structures of abzymes that catalyze important classes of chemical reactions, cocaine-binding antibodies, and cocaine esterases in an iterative cycle of structure determination, redesign of ligands, and mutagenesis. The progress of these projects is in various stages, from purified proteins, to crystallized proteins, to structures in refinement, consistent with a productive five-year plan. Given that catalytic antibodies have now been produced that are as efficient as natural enzymes, the next goal is to make further progress in increasing the efficiency and specificity of enzymes of biomedical, biotechnological, and chemical importance. In this way, the enormous potential power of the immune system can be harnessed to rapidly develop tailor-made catalysts in a few weeks, compared to the billions of years it has taken for evolution of natural enzymes.

描述（申请人提供）：抗体的结构见解 催化对于新颖的设计和改善有效至关重要 生物催化剂。因此，这种更新的主要目标是专注于催化 将直接影响公共卫生问题会产生直接影响的抗体 通用化学和生物技术实用程序，或将提供机械 提高催化效率或特异性的指南。结构 将合并生化，化学和理论方法 提供新的配体设计或诱变的方向。下面的抗体 研究催化了周环，消除，转移和酯酶反应。 从这些abzyme晶体结构得出的一般原理将是 专门用于增强可卡因结合和降解活动 人源化抗体和人类酶。可卡因降解抗体具有 可卡因成瘾的免疫疗法的巨大治疗潜力， 从而减轻了这种药物造成的社会和经济负担。这 个体特定的目的是确定abzymes的X射线晶体结构 催化了重要的化学反应类别，可卡因结合 抗体和可卡因酯酶在迭代的结构循环中 确定，配体的重新设计和诱变。这些进展 项目处于各个阶段，从纯化的蛋白质到结晶 蛋白质，改进的结构，与五年生产性一致 计划。鉴于现在已经生产了催化抗体 作为天然酶有效，下一个目标是进一步进步 提高生物医学酶的效率和特异性， 生物技术和化学重要性。这样，巨大的潜力 可以利用免疫系统的功率快速发展量身定制的 几周后的催化剂，相比之下 天然酶的进化。