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Studies to understand and exploit 10-membered enediyne biosynthesis

研究了解和利用 10 元烯二炔生物合成

基本信息

批准号：
10092819
负责人：
GEORGE NEAL PHILLIPS
金额：
$ 51.62万
依托单位：
UNIVERSITY OF KENTUCKY
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-03-01 至 2023-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10092819
关键词：
Achievement Alkylation Amines Anabolism Anthraquinones Anti-Infective Agents Antibodies Antitumor Natural Products Architecture Biochemical Biogenesis Bioinformatics Biotin Chemical Structure Chemistry Clinical Collaborations Complement Complex Crystallization Cyclization Development Dynemicin Enzymatic Biochemistry Enzymes Family member Foundations Genetic Hybrids Hydroxylation Iodination reaction Ligands Mixed Function Oxygenases Modality Modification Molecular Monoclonal Antibodies Natural Products Nucleotides Polyenes Proteins Reaction Reagent Route Series Structure Sulfur Trisaccharides analog anti-cancer base cancer therapy catalyst chemical genetics clinical development design enzyme pathway genetic approach glycosylation glycosyltransferase innovation insight non-Native novel novel strategies oxidation polyketide synthase prototype structural biology structural genomics sugar targeted agent thiosugar tool tumor

项目摘要

ABSTRACT The 10-membered enediynes [exemplified by calicheamicin (CLM), esperamicin (ESP) and dynemicins (DYN)] are arguably among the most renowned natural products (NPs) discovered to date by virtue of their unprecedented complex molecular architectures, notable anticancer and anti-infective potencies and, in the case of CLM, demonstrated clinical utility. The current study builds on a longstanding collaborative effort of achievement and discovery relating to key aspects of 10-membered enediyne biosynthesis as well as parallel innovative efforts to co-opt key biosynthetic catalysts for synthetic applications. The studies put forth will take advantage of this strong foundation and a powerful combination of genetic, biochemical, chemical and protein structural tools to elucidate the remaining unusual biosynthetic transformations and to exploit select catalysts for enediyne non-native modification. Specifically, aims 1 and 2 will focus on extending our understanding of the fundamental steps of enediyne core biosynthesis common to CLM/DYN/ESP, DYN anthraquinone biosynthesis and a selected set of unique tailoring reactions (CLM/ESP thiosugar sulfur installation and aminopentose N- alkylation, ESP C6-hydroxylation and O-glycosylation). In parallel, aim 3 will focus on tactical structural studies to augment both aims 1 and 2 and the structural study of ‘unknowns’ to facilitate functional annotation. Additional studies in aim 2 with key catalysts and corresponding non-native substrates are designed to assess the potential for strategic installation of chemoselective handles to enable novel approaches for facile, mild bioconjugation of CLM to tumor-targeting mAbs (in collaboration with Pfizer).

摘要 10-元烯二炔[例如加利车霉素（CLM）、埃斯帕霉素（ESP）和动力霉素（DYN）] 可以说是迄今为止发现的最著名的天然产品（NP）之一，前所未有的复杂分子结构，显著的抗癌和抗感染效力，的CLM，证明了临床实用性。目前的研究建立在长期合作的基础上，与10元烯二炔生物合成的关键方面有关的成就和发现以及平行的创新的努力，以增选关键的生物合成催化剂的合成应用。提出的研究将采取这种强大的基础和遗传，生化，化学和蛋白质的强大组合的优势结构工具来阐明剩余的不寻常的生物合成转化，并利用选择的催化剂，烯二炔非天然修饰。具体而言，目标1和2将侧重于扩大我们对烯二炔核心生物合成的基本步骤与CLM/DYN/ESP、DYN蒽醌生物合成相同和一组选定的独特的剪裁反应（CLM/ESP硫代糖硫安装和氨基戊糖N- 烷基化、ESP C6-羟基化和0-糖基化）。与此同时，aim 3将侧重于战术结构研究加强目标1和目标2以及“未知数”的结构研究，以便于功能注释。额外目的2中的研究采用关键催化剂和相应的非天然底物，用于化学选择性手柄的战略性安装，以实现用于以下的简单、温和的生物缀合的新方法： CLM到肿瘤靶向mAb（与辉瑞公司合作）。