A Tool for synthetic post-translational modifications of cysteines

半胱氨酸合成翻译后修饰的工具

• 批准号: 10378706
• 负责人: Tomislav Rovis
• 金额: $ 19.63万
• 依托单位: COLUMBIA UNIV NEW YORK MORNINGSIDE
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-04-01 至 2023-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10378706
• 关键词: Amino Acids; Biology; Carbon; Catalysis; Communities; Complex; Coupling; Cysteine; Goals; Health; Incentives; Investigation; Methods; Modification; Nickel; Oligopeptides; Pathway interactions; Peptides; Phosphines; Phosphorylation; Phosphotyrosine; Positioning Attribute; Post-Translational Protein Processing; Principal Investigator; Proteins; Protocols documentation; Research; Scaffolding Protein; Site; Sulfhydryl Compounds; Therapeutic Agents; desulfurization; programs; small molecule; tool; unnatural amino acids

Principal Investigator/Program Director (Last, First, Middle): Rovis, Tomislav A tool for synthetic post-translational modifications of cysteines Abstract- The ability to selectively install amino acid residues within a protein scaffold has been monumental in deconvoluting the central dogma of biology. Specifically, introducing unnatural amino acids (UAAs) have aided in the investigation of mechanistic studies within proteins, and has incentivized the community to develop synthetic methods for installing UAAs. Within this field, it is valuable to be able to install UAAs that contain post-translational modifications (PTMs), especially those that are native to biology. In particular, the understanding of protein phosphorylation is still limited by the lack of mechanistic understanding of phosphorylation pathways. Therefore, there is an impetus to synthetically incorporate phosphorylated amino acids into a protein scaffold. We aim to create a method to synthetically install natural PTMs within a protein scaffold using Cys thiols and photoredox catalysis. Herein, we propose a method to utilize Cys-containing peptides as a precursor for carbon-centered radicals, which can be further functionalized via nickel catalysis. In this regard, desulfurization can occur through the β-scission of the Cys thiyl radical and a phosphine, generating a new C-centered radical. By choosing the coupling partner, a variety of aryl functionality can be incorporated selectively at the Cys position. In addition, aryl functionality equipped with natural PTMs can be directly incorporated into a protein scaffold. The specific goals of this research are as follows: 1) Develop a site-selective arylation protocol for conversion of cysteine to phosphotyrosine 2) Extend this method to Cys modification in oligopeptides and proteins

首席研究员/项目主管（最后、第一、中）：Rovis, Tomislav