CAREER: New Chemical Tools for Probing the Biological Significance of Hydrogen Sulfide and Hydrogen Selenide

该奖项的部分资金来自2021年美国救援计划法案（公法117-2）。在化学系生命过程化学项目的支持下，维克森林大学的约翰·卢克什正在开发新的化学工具，以研究硫化氢（H2S）和硒化氢（H2Se）的生物学意义。鉴于这两种气体在历史上被视为与人类生物学几乎无关的有毒污染物，因此对其生物学功能，细胞靶点以及生产和代谢的全面了解仍然难以捉摸。该提案的总体目标是通过分子设计和开发新的分子支架来回答这些具体问题，这些分子支架可以在生物相关条件下有效检测或递送H2S和H2Se。从事这些工作的学生将接触到各种各样的主题和技术，在化学和生物学的不断扩大的接口，因为他们解锁一个新的前沿氧化还原信号社区。该计划还整合了旨在与北卡罗来纳州温斯顿-塞勒姆当地社区联系的多层次方法。这些努力包括为当地中学生开设有趣和互动的化学讲座，以及积极招募代表性不足的少数民族大学生到维克森林大学担任研究职位。为了促进对H2S和H2Se的流行和生理意义的新调查，该项目旨在设计新的化学工具，以帮助在生物相关条件下提供或检测这两种气体。具体而言，将采用全新的化学方法，通过分析物引发的环化反应从含硫基序中选择性释放H2S。这种独特的机制途径将被用来解锁一个家庭的捐助者，有可能推进硫化物信号研究领域，通过他们的能力，以目标特定的组织和细胞器;选择性地响应刺激上调疾病;和自我报告他们的真实的时间交付H2S通过并发荧光团组装。该项目也代表了一个开创性的努力，以产生新的捐助者和反应为基础的探针特异性H2Se。鉴于此类化合物的稀缺性，这种新的化学方法有可能加速分子信号传导研究，并引发一个旨在探索H2Se的化学生物学和先天生理功能的新兴科学领域。包括其促进氧化后该奖项反映了NSF的法定使命，并通过使用基金会的智力价值进行评估，被认为值得支持和更广泛的影响审查标准。

This award is funded in part under the American Rescue Plan Act of 2021 (Public Law 117-2).With support of the Chemistry of Life Processes Program in the Division of Chemistry, John Lukesh of Wake Forest University is developing new chemical tools to investigate the biological significance of hydrogen sulfide (H2S) and hydrogen selenide (H2Se). Given that both gases were historically dismissed as toxic pollutants with little relevance to human biology, a comprehensive understanding of their biological functions, cellular targets, and production and metabolism remains elusive. The overall goal of this proposal is to answer these specific questions through molecular design and the development of new molecular scaffolds that effectively detect or deliver H2S and H2Se under biologically relevant conditions. Students engaged in these efforts will be exposed to a wide-variety of topics and techniques at the ever-widening interface of chemistry and biology as they unlock a new frontier to the redox signaling community. This program also integrates a multi-tiered approach aimed at connecting with the local community of Winston-Salem, NC. These efforts include the development of fun and interactive chemistry lectures for local middle school students and the active recruitment of underrepresented minority college students to research positions at Wake Forest University. To facilitate new investigations into the prevalence and physiological significance of H2S and H2Se, this project aims to engineer new chemical tools to assist in the delivery or detection of both gases under biologically relevant conditions. Specifically, fundamentally new chemistry will be employed to selectively release H2S from sulfur-containing motifs via an analyte-triggered cyclization reaction. This unique mechanistic pathway will be used to unlock a family of donors that have the potential to advance the field of sulfide signaling research through their ability to target specific tissues and organelles; selectively respond to stimuli upregulated in disease; and self-report their real time delivery of H2S through concurrent fluorophore assembly. This project also represents a pioneering effort to generate new donors and reaction-based probes specific to H2Se. Given the scarcity of such compounds, this new chemistry has the potential to accelerate molecular signaling research, and to spark an emerging area of science aimed at exploring the chemical biology and innate physiological functions of H2Se, including its propensity to promote oxidative post-translational modifications.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.