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）：最近人们对核糖体肽天然产物（RIPP）代表地球上主要的生物活性天然产物之一。这些化合物几乎在细菌中几乎普遍发现，它们在其中放置了各种作用，包括法定人信号，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中的关键参与者。也许更重要的是，Ripps提供了一块巨大的翻译后机械库，可用于设计类似药物的化合物。它们很容易通过理性的工程和所需属性的优化进行操纵。在此提案中，我们将使用这种多样化的Ripp Biosynthetic机械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在设计和发现新的抗生素中。我们的具体目的是：1）使用化学，生化和遗传学方法来表征独特的RIPP翻译后酶； 2）改善异源宿主中的复合产生和模拟合成； 3）通过实施新型生物测定方法来发现新的抗生素。