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

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 高限制性多肽大环的合成和高效台式进化 大自然。在接下来的五年里，这些努力将在两个主要项目领域进行。在第一个项目中 我们将使用核糖体多肽天然产物生物合成途径中的酶来修饰mRNA 展示多肽文库。这项工作的关键将是继续开发显示耦合分析 用于酶修饰，将被用来阐明酶的混杂。在第二个项目区，这些 文库将被用于针对一组集中的治疗靶点选择新的大环肽抑制剂 和情结。目标-配体络合物的结构表征将揭示大环原理 并阐明针对这些具有挑战性的接口的新战略。这项工作是 有望为基于大环的多肽疗法的开发提供新的途径和技术。

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 and efficient benchtop evolution of highly constrained peptide macrocycles similar to those used in nature. Over the next five years, these efforts will be divided between two main project areas. In the first project area, we will use enzymes take from ribosomal peptide natural product biosynthetic pathways to modify mRNA display libraries of peptides. Essential to this work will be the continued development of display-coupled assays for enzyme modification that will be used to elucidate enzyme promiscuity. In the second project area, these libraries will be used to select novel macrocyclic peptide inhibitors against a focused set of therapeutic targets and complexes. Structural characterization of target-ligand complexes will uncover principles of macrocycle engagement and elucidate new strategies for targeting these otherwise challenging interfaces. This work is expected to yield new avenues and technologies for development of peptide macrocycle-based therapeutics.