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Generation and Solution Reactivity of Small Molecule Sulfur-based Signaling Agents

小分子硫基信号剂的生成和溶液反应性

基本信息

批准号：
1900285
负责人：
John Toscano
金额：
$ 50万
依托单位：
Johns Hopkins University
依托单位国家：
美国
项目类别：
Standard Grant
财政年份：
2019
资助国家：
美国
起止时间：
2019-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://www.nsf.gov/awardsearch/showAward?AWD_ID=1900285&HistoricalAwards=false
关键词：
Generation Solution Reactivity Small Molecule

项目摘要

With this award, the Chemical Structure, Dynamics, and Mechanisms-B Program support of the research of Professor John P. Toscano of the Chemistry Department at Johns Hopkins University. The research involves the generation and solution reactivity of biologically-relevant, sulfur-based, small molecules such as hydrogen sulfide (H2S) and hydropersulfides (RSSH). Hydrogen sulfide (H2S) is a signaling agent whose effects in the body have been well documented. For example, H2S acts as a neuromodulator in the brain and may have applications in the treatment of neurodegenerative disorders such as Parkinson's and Alzheimer's disease. The chemical mechanisms responsible for these effects are poorly understood. Recent reports indicate that the biological activity of hydrogen sulfide may actually be attributed to hydropersulfides and so this will also be tested. The project gives broad, comprehensive training to both graduate and undergraduate students, preparing them for future jobs in both industry and academia. An afterschool science outreach experience for middle school students in Baltimore, MD is in development.Hydropersulfides are involved in important post-translational modifications in several enzymes and proteins. In addition, small molecule hydropersulfides such as cysteine hydropersulfide and glutathione hydropersulfide have been detected in tissues, cells, and plasma at significant concentrations. Unfortunately, hydropersulfides are inherently difficult to study in aqueous solution, as they are unstable and decomposes rapidly into a variety of species. As a result, hydropersulfides are typically generated in situ. Although several strategies for hydropersulfide generation have been reported, there is still an unmet need for the development of new methods for the efficient and controlled production of hydropersulfides without the involvement of exogenous reagents. The development of novel hydropersulfide precursors and protein persulfidating reagents is a focus of this project. Previous work has demonstrated that another small molecule biological signaling agent, nitroxyl (azanone, HNO), elicits much of its activity through modification of protein thiols. Given the expected reactivity of hydrogen sulfide and hydropersulfides, reaction with HNO is anticipated and may be relevant to the observed biological reactions. The mechanism of this reaction and the resulting products will be investigated thoroughly. Likewise, the reaction of hydrogen sulfide with HNO will also be examined. The mechanisms and products of these reactions, utilizing standard analytical tools as well as membrane inlet mass spectrometry, will be studied.This award reflects NSF's statutory mission and has been deemed worthy of support through evaluation using the Foundation's intellectual merit and broader impacts review criteria.

有了这个奖项，化学结构，动力学和机制-B计划支持约翰霍普金斯大学化学系教授约翰P.托斯卡诺的研究。该研究涉及生物相关的硫基小分子（如硫化氢（H2S）和氢过硫化物（RSSH））的生成和溶液反应性。硫化氢（H2S）是一种信号剂，其在体内的作用已被充分证明。例如，H2S在大脑中充当神经调节剂，并且可以应用于治疗神经退行性疾病，例如帕金森病和阿尔茨海默病。对这些影响的化学机制知之甚少。最近的报告表明，硫化氢的生物活性实际上可能归因于氢过硫化物，因此也将对其进行测试。该项目为研究生和本科生提供广泛，全面的培训，为他们未来在工业和学术界的工作做好准备。在马里兰州的巴尔的摩，一项针对中学生的课外科学推广活动正在进行中。过硫化物参与了几种酶和蛋白质的重要翻译后修饰。此外，已在组织、细胞和血浆中检测到显著浓度的小分子氢过硫化物，如半胱氨酸氢过硫化物和谷胱甘肽氢过硫化物。不幸的是，氢过硫化物在水溶液中固有地难以研究，因为它们不稳定并且迅速分解成各种物质。因此，过硫化物通常原位生成。尽管已经报道了几种产生过氧化氢的策略，但仍然需要开发用于在不涉及外源试剂的情况下有效和受控地生产过氧化氢的新方法。本项目的重点是开发新型过硫氢前体和蛋白质过硫化试剂。以前的工作已经证明，另一种小分子生物信号传导剂硝酰基（氮杂酮，HNO），通过修饰蛋白质巯基来增强其活性。考虑到硫化氢和氢过硫化物的预期反应性，预期与HNO反应，并且可能与观察到的生物反应相关。该反应的机理和所产生的产物将被彻底研究。同样，硫化氢与HNO的反应也将被检查。将利用标准分析工具以及膜入口质谱法研究这些反应的机制和产物。该奖项反映了NSF的法定使命，并且通过使用基金会的知识价值和更广泛的影响进行评估，被认为值得支持。审查标准。

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Photochemical Release of Hydropersulfides

氢过硫化物的光化学释放

DOI：
10.1021/acs.joc.2c01049
发表时间：
2022
期刊：
The Journal of Organic Chemistry
影响因子：
0
作者：
Aggarwal, Sahil C.;Khodade, Vinayak S.;Porche, Sarah;Pharoah, Blaze M.;Toscano, John P.
通讯作者：
Toscano, John P.

Hydropersulfides Inhibit Lipid Peroxidation and Protect Cells from Ferroptosis