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

基本信息

批准号：
10674773
负责人：
Albert A Bowers
金额：
$ 38.93万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-05 至 2027-08-31
项目状态：
未结题

项目摘要

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.

基于天然产物的大环的化学酶合成，作用方式和演变天然肽大环的能力与具有挑战性的蛋白质靶标，例如蛋白质界面和转录因子。我们实验室的目标是使用从天然产品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。我们将使用合并的化学和酶促方法进行高度约束肽大环的合成和有效的台式演化类似于自然。在接下来的五年中，这些努力将在两个主要项目区域之间进行分配。在第一个项目中区域，我们将使用酶从核糖体肽天然产物生物合成途径中采取酶来修饰mRNA 显示肽的库。这项工作至关重要的是展示耦合测定的持续开发用于修饰的酶修饰，该酶将用于阐明酶滥交。在第二个项目领域，这些图书馆将用于选择新型的大环肽抑制剂，以针对集中的一组治疗靶标和复合物。目标配体配合物的结构表征将发现大环的原理参与并阐明针对这些原本具有挑战性的界面的新策略。这项工作是预计将产生新的途径和技术，以开发肽大环的治疗疗法。