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: 10798737
• 负责人: Albert A Bowers
• 金额: $ 2.55万
• 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 2027-08-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10798737
• 关键词: Anabolism; Area; Binding; Biological Assay; Chemicals; Complex; Coupled; Development; Enzymes; Evolution; Goals; Libraries; Ligands; Malignant Neoplasms; Messenger RNA; Methods; Modification; Natural Products; Natural Products Chemistry; Nature; Pathway interactions; Peptide Library; Peptides; Preparation; Proteins; Ribosomes; Therapeutic; Work; inhibitor; insight; natural product inspired; novel; novel therapeutics; parent grant; peptide natural products; scaffold; technology development; therapeutic target; transcription factor

Chemoenzymatic Synthesis, Mode of Action and Evolution of Natural Product-based Macrocycles (Parent Grant) 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.

天然产物大环化合物的化学酶法合成、作用方式及进化 （家长津贴） 天然肽大环化合物是有前途的下一代治疗剂，由于它们的结合能力， 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 利用天然产物生物合成的见解和化学知识，促进发现和开发 新的天然产物类肽大环化合物。我们将使用化学和酶的结合 用于合成和有效的实验室进化高度受限的肽大环化合物的方法， 那些在自然界中使用的。在今后五年中，这些努力将分为两个主要项目领域。在 第一个项目领域，我们将利用酶从核糖体肽天然产物生物合成途径 来修饰肽的mRNA展示文库。这项工作的关键是继续发展 用于酶修饰的显示偶联测定，其将用于阐明酶混杂性。在 第二个项目领域，这些文库将用于选择新的大环肽抑制剂， 集中的治疗靶点和复合物。靶-配体复合物的结构表征 将揭示大循环参与的原则，并阐明针对这些目标的新策略 其他具有挑战性的接口。这项工作预计将产生新的途径和技术， 开发基于肽大环的治疗剂。

项目成果

Enzymatic Macrolactamization of mRNA Display Libraries for Inhibitor Selection.

用于抑制剂选择的 mRNA 展示文库的酶促大内酰胺化。

• DOI: 10.1021/acschembio.2c00828
• 发表时间: 2023
• 期刊: ACS chemical biology
• 影响因子: 4
• 作者: Bowler,MatthewM;Glavatskikh,Marta;Pecot,ChadV;Kireev,Dmitri;Bowers,AlbertA
• 通讯作者: Bowers,AlbertA

Expanding the Chemical Diversity of Genetically Encoded Libraries.

• DOI: 10.1021/acscombsci.0c00179
• 发表时间: 2020-12-14
• 期刊: ACS combinatorial science
• 作者: Iskandar SE;Haberman VA;Bowers AA
• 通讯作者: Bowers AA