Peptide-Conjugated Palladium Oxidative Addition Complexes for Site-Selective Arylation Chemistry

用于位点选择性芳基化化学的肽缀合钯氧化加成络合物

• 批准号: 10677379
• 负责人: Dennis Kutateladze
• 金额: $ 6.91万
• 依托单位: MASSACHUSETTS INSTITUTE OF TECHNOLOGY
• 依托单位国家: 美国
• 财政年份: 2023
• 资助国家: 美国
• 起止时间: 2023-08-01 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10677379
• 关键词: Active Sites; Affinity; Air; Antibody-drug conjugates; Binding; Binding Proteins; Binding Sites; Biocompatible Materials; Biological Process; Biology; Chemicals; Chemistry; Complex; Coupling; Cysteine; Derivation procedure; Development; Engineering; Faculty; Goals; Health; Human; Label; Laboratories; Link; Lysine; Mass Spectrum Analysis; Massachusetts; Medicine; Metals; Methods; Modernization; Modification; Natural Products; Nature; Nucleic Acids; Organometallic Chemistry; Palladium; Peptide Synthesis; Peptides; Pharmaceutical Preparations; Pharmacologic Substance; Physiological; Polyamines; Positioning Attribute; Post-Translational Protein Processing; Preparation; Process; Production; Proteins; R peptide; Reaction; Reagent; Research; Secure; Site; Structure; Structure-Activity Relationship; Techniques; Technology; Training; United States National Institutes of Health; Universities; aqueous; aryl halide; catalyst; combinatorial; drug discovery; drug structure; frontier; human disease; interest; metalloenzyme; novel therapeutics; peptide structure; polyol; post-doctoral training; protein aminoacid sequence; protein degradation; protein function; skills; small molecule

PROJECT SUMMARY/ABSTRACT The site-selective chemical modification of biomolecules including proteins and biologically active small molecules is currently recognized as an important and unmet challenge in chemical biology. While current strategies for chemical protein modification have proven highly enabling for a variety of applications related to mechanistic biology and the production of biomaterials and pharmaceuticals, site-selective approaches are rare and highly valued. The first Aim of this proposal details a strategy to access well-defined site-selectively labeled protein conjugates for varied applications across chemical biology. Central to the thesis of this proposal is the use of palladium oxidative addition complexes that have been previously shown by the Buchwald and Pentelute labs to efficiently engage protein targets in C–heteroatom arylation reactions under mild physiological conditions. The covalent derivatization of these palladium-based reagents with peptide sequences that bind a protein of interest is proposed as a strategy to achieve site-selective protein cysteine arylation in both intra- and intermolecular contexts. These technologies are expected to enable a myriad of applications including the formation of site-selectively modified antibody-drug-conjugates and selective protein degrading platforms. In an effort to significantly simplify drug structure-activity-relationship studies and produce valuable probes for mechanistic biology, the second Aim of this proposal extends peptide-conjugated palladium arylation chemistry to the regioselective modification of biologically-active small molecules. While current approaches to site- selective small molecule derivatization generally operate on a narrow range of substrate classes and lack generality, this proposal aims to deliver a general and highly modular approach to site-selective arylation of complex polyol and polyamine targets, reliant on the well-defined secondary structure that peptide conjugates impart about the Pd active site. Overall, the proposed the site-selective bioconjugation approach detailed in this proposal will have the potential to be highly impactful for chemical biology by enabling powerful discovery platforms for mechanistic biology and pharmaceutical applications. The objectives of this proposal are directly related to the advancement of human health, are well aligned with the aims of the NIH. With the ultimate goal of securing an academic position at a major research university, the Buchwald and Pentelute laboratories at the Massachusetts Institute of Technology represent an ideal setting in which to conduct my postdoctoral training in organometallic bioconjugation. The Buchwald lab’s expertise in metal- catalyzed cross-coupling and its application to C–heteroatom bond forming processes and the Pentelute lab’s focus within chemical biology and peptide synthesis will be instrumental in the execution of the proposed research. During my training, I will gain crucial skills in chemical biology and organometallic chemistry that will compliment my background in enantioselective organocatalysis, and prepare me to excel in a faculty position.

项目摘要/摘要 生物分子（包括蛋白质和生物活性小的生物分子）的现场选择性化学修饰 目前，分子被认为是化学生物学中的重要且未满足的挑战。当前 事实证明，化学蛋白质修饰的策略对与与 机械生物学以及生物材料和药品的生产，现场选择方法很少见 并受到高度重视。该提案的第一个目的详细介绍了访问定义明确标签的策略 蛋白质结合物用于化学生物学的各种应用。该提议论文的核心是 Buchwald和Pentelute先前已显示的钯氧化添加复合物的使用 实验室在轻度生理条件下有效地使蛋白质靶标参与C-杂摩芳基化反应。 这些基于钯的试剂与肽序列的共价衍生化结合了 提出了兴趣作为实现位点选择性蛋白质半胱氨酸芳基化的一种策略 分子间环境。这些技术有望实现无数的应用 位点选择修饰的抗体 - 毒与偶联物和选择性蛋白质降解平台的形成。在 努力显着简化药物结构 - 活性研究研究，并为 机械生物学，该提案的第二个目的扩展了肽偶联的钯化学 调节生物活性小分子的修改。而目前的现场方法 - 选择性小分子衍生化通常在狭窄范围的底物类中运行，并且缺乏 一般性，该提案旨在提供一种一般且高度模块化的方法来实现现场选择性芳基化 复杂的多元醇和多胺靶标，依赖于定义明确的二级结构，使缀合物胡椒缀合物 授予PD活动站点。总体而言，提议的现场选择性生物结合方法在此详细介绍 提案有可能通过实现强大的发现来对化学生物学产生重大影响 机械生物学和药物应用的平台。该提议的目标是直接 与人类健康的进步有关，与NIH的目的一致。 Buchwald的最终目标是确保在一所大型研究中获得学术职位 马萨诸塞州理工学院的五角星实验室代表了一个理想的环境 进行有机生物缀合的博士后培训。布赫瓦尔德实验室在金属方面的专业知识 - 催化的交叉耦合及其应用于C型糖粘合键形成过程和Pentelute Lab的 化学生物学和胡椒合成中的重点将有助于执行建议 研究。在培训期间，我将获得化学生物学和有机化学的关键技能 称赞我在对映选择性组织分析方面的背景，并为我准备在教师职位上表现出色。