Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles

天然产物大环化合物的化学酶法合成、作用方式和演化

• 批准号: 10241273
• 负责人: Albert A Bowers
• 金额: $ 38.34万
• 依托单位: UNIV OF NORTH CAROLINA CHAPEL HILL
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-09-05 至 2022-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10241273
• 关键词: Anabolism; Area; Binding; Biological; Chemicals; Complex; Development; Directed Molecular Evolution; Enzymes; Evolution; FOXM1 gene; Goals; Laboratories; Malignant Neoplasms; Messenger RNA; Methods; Natural Products; Natural Products Chemistry; Nature; Oncogenic; Pathway interactions; Peptides; Preparation; Proteins; Research; Ribosomes; Structure; Therapeutic; Work; analog; anticancer activity; base; improved; inhibitor/antagonist; insight; novel therapeutics; scaffold; technology development; therapeutic target; transcription factor

Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles Natural peptide macrocycles are promising next-generation therapeutics, due to their abilities to bind to challenging protein targets, such as protein interfaces and transcription factors. The goal of our lab is to use insights and chemistries from natural product biosynthesis to facilitate the discovery and development of new natural product-like peptide macrocycles. We will use a combined chemical and enzymatic approach for synthesis of highly constrained peptide macrocycles similar to those used in nature. Over the next five years, these efforts will be divided amongst three project areas. In the first project, we develop a chemoenzymatic platform for the preparation of analogs of the thiopeptide natural products. We further exploit this platform to examine new, diversity generating enzymes from complimentary ribosomal natural product pathways. In the second project, we will investigate the multi-faceted biological activities of thiopeptides and develop potent and selective inhibitors of the oncogenic transcription factor FoxM1. A major thrust of this research will be structure elucidation of thiopeptides bound to FoxM1. In the final project, we combine enzymes from ribosomal peptide natural product with mRNA display to allow laboratory scale directed evolution of new peptide macrocycle inhibitors. This work is expected to yield new avenues and technologies for development of peptide macrocycle- based therapeutics.

天然产物大环化合物的化学酶法合成、作用方式及进化 天然肽大环化合物是有希望的下一代治疗剂，这是由于它们能够结合至 具有挑战性的蛋白质靶点，如蛋白质界面和转录因子。我们实验室的目标是 从天然产物生物合成的见解和化学，以促进新的发现和发展， 天然产物类肽大环化合物。我们将使用化学和酶法相结合的方法， 合成与自然界中使用的那些类似的高度受限的肽大环。在接下来的五年里， 这些工作将分为三个项目领域。在第一个项目中，我们开发了一种化学酶， 本发明提供了制备硫肽天然产物类似物的平台。我们进一步利用这个平台， 研究新的，多样性产生酶从互补核糖体天然产物途径。在 第二个项目，我们将研究硫肽的多方面生物活性，并开发有效的， 致癌转录因子FoxM1的选择性抑制剂这项研究的一个主要方向是结构 说明与FoxM1结合的硫肽。在最后的项目中，我们将核糖体肽中的联合收割机酶 允许实验室规模定向进化新肽大环化合物的具有mRNA展示的天然产物 抑制剂的本研究为肽类大环化合物的开发提供了新的途径和技术， 基于治疗。