Chemical Tools for Probing Cysteine Sulfenation and Sulfination Redox Biology

用于探测半胱氨酸磺化和磺化氧化还原生物学的化学工具

基本信息

批准号：
10658440
负责人：
Kate Suzanne Carroll
金额：
$ 39.61万
依托单位：
UNIVERSITY OF FLORIDA
依托单位国家：
美国
项目类别：
财政年份：
2012
资助国家：
美国
起止时间：
2012-08-01 至 2026-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10658440
关键词：
Address Alkynes Amines Amino Acids Aminoacylation Biological Process Biology Blood Cancer cell line Cells Chemicals Chemistry Computing Methodologies Coupled Cultured Cells Cysteine Data Development Disease Drug Kinetics Escherichia coli Evaluation Fluorescence Microscopy Funding Genetic Glutathione Homeostasis Human Hydrogen Peroxide Inherited Kinetics Label Libraries Ligands Light Link Mammalian Cell Mediating Medicine Methods Modification Molecular Mutation Oxidation-Reduction Pharmaceutical Preparations Pharmacology Play Preparation Property Proteins Proteome Proteomics Reaction Regulation Reporting Research Resolution Role Signal Transduction Site Source Sulfenic Acids Sulfhydryl Compounds Sulfoxide Testing Variant analog chemical resource chemoproteomics cysteine sulfinic acid cysteinesulfenic acid design diketone drug discovery improved innovation novel protein function scaffold small molecule spatiotemporal tool

项目摘要

PROJECT SUMMARY Post-translational changes in the redox state of cysteine residues can rapidly and reversibly alter protein function, modulating biological processes and drug pharmacology. During the last funding period, our lab reported several innovations in organosulfur chemistry, small-molecule tools, and computational methods for proteomic analysis that dramatically improved selectivity, cellular application, and site-specific quantitation of the cysteine redoxome (J. Am. Chem. Soc., 2017; Nat. Chem. Biol., 2018; Nat. Chem., 2021; Nat. Comm., 2022). Application of these chemoproteomic methods has contributed to meaningful discovery of new paradigms in redox biology (Nat. Cell Biol., 2019; Cell Metab., 2019; Blood Adv., 2020; Nat. Comm., 2021; Redox Biol., 2021 & 2022; Proc. Natl. Acad. Sci., 2022) and raise interesting new questions about the links between the cellular redox landscape, molecular thiol-based redox switches, and the emerging field of redox medicine. Herein, the following three Specific Aims are proposed: Development and application of 1) chemical methods to address spatiotemporal control in redox signaling; 2) genetic incorporation of oxidized cysteine in proteins to pinpoint molecular mechanisms underlying thiol-based redox regulation; and 3) nucleophile-fragment libraries to discover covalent ligands that target redox- regulated proteins in the cysteinome. Strong preliminary data demonstrate that studies proposed herein are both promising and feasible in our hands. Deliverables resulting from these studies include: 1) valuable new chemical biology approaches to understand fundamental mechanisms in thiol-based redox signaling, and 2) novel chem- ical matter that can be mined as a source of small-molecule probes and as starting points for drug discovery.

项目摘要半胱氨酸残基氧化还原状态的翻译后变化可以迅速而可逆地改变蛋白质功能，调节生物学过程和药物学。在最后一个资金期间，我们的实验室报告了几个有机硫化学，小分子工具和蛋白质组学分析的计算方法的创新大都会改善了半胱氨酸氧化还原氧化氧化物的选择性，细胞应用和特定地点的定量（J.Am。Chem。Soc。，2017;Nat。Chem。Biol。，2018;Nat。Chem。，2021;Nat。Comm。，2022）。这些应用化学蛋白质组学方法有助于有意义地发现氧化还原生物学中的新范式（NAT。细胞 Biol。，2019年； Cell Metab。，2019年；血统，2020年；纳特。 Comm。，2021； Redox Biol。，2021年和2022年； Proc。纳特。学院。 Sci。，2022），并提出了有关细胞氧化还原景观之间联系的有趣的新问题基于硫醇的氧化还原开关和氧化还原医学的新兴领域。在此，以下三个特定目标提出：开发和应用1）化学方法解决氧化还原时时空控制的化学方法信号传导； 2）将氧化半胱氨酸在蛋白质中的遗传掺入以查明分子机制的确定基于硫醇的氧化还原调节； 3）亲核碎片库，以发现靶向氧化还原的共价配体在半胱氨酸组中调节的蛋白质。强大的初步数据表明，此处提出的研究都是我们手中有希望和可行的。这些研究产生的可交付成果包括：1）有价值的新化学物质生物学方法了解基于硫醇的氧化还原信号传导中的基本机制，以及2）新型化学可以将其作为小分子探针的来源和药物发现的起点进行开采。