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.

天然产物大环的化学酶合成、作用方式及演化

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