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分子的位点选择性化学修饰 分子目前被认为是化学生物学中重要的和未满足的挑战。虽然目前的 化学蛋白质修饰的策略已被证明非常适用于与以下相关的各种应用： 机械生物学和生物材料和药物的生产，位点选择性方法是罕见的 而且价值不菲该提案的第一个目标详细介绍了一种策略，以访问定义明确的站点选择性标记 蛋白质结合物在化学生物学中的各种应用。这一建议的中心论点是， 使用钯氧化加成络合物，其先前已由Buchwald和Pentelute 实验室在温和的生理条件下有效地参与C-杂原子芳基化反应的蛋白质目标。 这些基于钯的试剂与肽序列的共价衍生化，所述肽序列结合以下蛋白质： 兴趣被提出作为一种策略，以实现位点选择性的蛋白质半胱氨酸芳基化， 分子间环境预计这些技术将使无数的应用程序，包括 形成位点选择性修饰的抗体-药物缀合物和选择性蛋白质降解平台。中 努力显著简化药物结构-活性-关系研究，并产生有价值的探针， 机械生物学，该提案的第二个目的扩展了肽共轭钯芳基化化学 涉及生物活性小分子的区域选择性修饰。虽然目前的方法，以网站- 选择性小分子衍生化通常在窄范围的底物类别上操作 一般来说，该提议旨在提供一种通用的和高度模块化的方法来位点选择性芳基化 复杂的多元醇和多胺靶点，依赖于肽缀合物的明确的二级结构， 传递关于Pd活性位点。总的来说，本文中详细介绍了所提出的位点选择性生物缀合方法。 该提案将有可能通过实现强大的发现而对化学生物学产生高度影响 机械生物学和制药应用的平台。这项建议的目的直接是 与人类健康的进步有关，与NIH的目标完全一致。 最终目标是在一所主要的研究型大学获得一个学术职位， 马萨诸塞州理工学院的Pentelute实验室是一个理想的环境， 进行有机金属生物共轭的博士后培训。布赫瓦尔德实验室在金属方面的专长- 催化的交叉偶联及其在C-杂原子键形成过程中的应用，以及Pentelute实验室的 化学生物学和肽合成的重点将有助于执行拟议的 research.在培训期间，我将获得化学生物学和有机金属化学方面的关键技能， 赞美我在对映选择性有机催化方面的背景，并为我在教师职位上的出色表现做好准备。