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天然产物大环的化学酶合成、作用方式及进化 天然多肽大环因其结合能力而成为下一代治疗药物。 挑战蛋白质靶标，如蛋白质界面和转录因子。我们实验室的目标是使用 来自天然产物生物合成的见解和化学，以促进新的发现和开发 天然产物样肽大环。我们将使用化学和酶相结合的方法 合成与自然界中使用的类似的高度受限制的多肽大环。在接下来的五年， 这些工作将在三个项目领域进行。在第一个项目中，我们开发了一种化学酶 硫肽天然产物类似物制备平台。我们进一步利用这个平台来 研究来自免费核糖体天然产物途径的新的、多样性产生酶。在 第二个项目，我们将研究硫肽的多方面生物活性，并开发有效的和 致癌转录因子FOXM1的选择性抑制物。这项研究的一个主要主题是结构 FOXM1结合硫代多肽的鉴定在最后一个项目中，我们结合了来自核糖体多肽的酶。 带有mRNA展示的天然产物允许实验室规模定向进化新的多肽大环 抑制剂。这项工作有望为多肽的开发提供新的途径和技术 以大周期为基础的疗法。

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.