Directed posttranslational modifications for drug design and discovery

用于药物设计和发现的定向翻译后修饰

• 批准号: 8821631
• 负责人: Eric W Schmidt
• 金额: $ 34.84万
• 依托单位: UNIVERSITY OF UTAH
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-04-01 至 2016-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8821631
• 关键词: Anabolism; Antibiotics; Area; Bacteria; Biochemical Genetics; Biological Assay; Biological Factors; Chemicals; Complex; Development; Drug Design; Engineering; Enzymes; Escherichia coli; Evolution; Exhibits; Figs - dietary; Goals; Growth; Health; Lead; Libraries; Ligands; Methods; Mutagenesis; Nature; Nisin; Novobiocin; Pathway interactions; Peptides; Pharmaceutical Preparations; Post-Translational Protein Processing; Production; Property; Quinolones; Reaction; Resistance; Role; Signal Transduction; Source; Technology; Testing; Toxic effect; Translating; Work; analog; base; chemical synthesis; cofactor; combat; design; drug development; drug discovery; improved; in vivo; innovation; novel; screening; tool

DESCRIPTION (provided by applicant): It has recently become appreciated that ribosomal peptide natural products (RiPPs) represent one of the major groups of bioactive natural products on Earth. The compounds are found nearly universally in bacteria, where they place diverse roles including quorum signaling, cofactor synthesis, and chemical defense. Most commonly, RiPPs exhibit potent antibiotic activity. They are key players in modern drug discovery and development. Perhaps more importantly, RiPPs present an enormous storehouse of posttranslational machinery that can be used to design drug-like compounds. They are readily manipulated for the rational engineering and optimization of desired properties. In this proposal, we will use this diverse RiPP biosynthetic machinery to better understand posttranslational enzymes, to optimize and engineer production platforms, and to develop technologies to better harness these complex pathways in the design and discovery of new antibiotics. Our specific aims are to: 1) Characterize unique RiPP posttranslational enzymes using chemical, biochemical, and genetic methods; 2) Improve compound production and analog synthesis in heterologous hosts; 3) Discover new antibiotics by implementing novel bioassays.

描述（由申请人提供）：最近人们认识到核糖体肽天然产物（RiPP）代表了地球上主要的生物活性天然产物类别之一。这些化合物几乎普遍存在于细菌中，它们发挥着不同的作用，包括群体信号、辅因子合成和化学防御。最常见的是，RiPP 表现出有效的抗生素活性。他们是现代药物发现和开发的关键参与者。也许更重要的是，RiPP 提供了一个巨大的翻译后机制库，可用于设计类药物化合物。它们很容易被操纵以进行合理的工程和所需性能的优化。在本提案中，我们将使用这种多样化的 RiPP 生物合成机制来更好地了解翻译后酶，优化和设计生产平台，并开发技术以更好地利用这些复杂的途径来设计和发现新的抗生素。我们的具体目标是： 1) 使用化学、生化和遗传学方法表征独特的 RiPP 翻译后酶； 2) 改善异源宿主中的化合物生产和类似物合成； 3) 通过实施新的生物测定来发现新的抗生素。