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·卢凯什正在开发新的化学工具，以研究硫化氢(硫化氢)和硒化氢(硫化氢)的生物学意义。鉴于这两种气体历来被认为是有毒污染物，与人类生物学几乎没有相关性，因此对它们的生物功能、细胞靶标以及生产和新陈代谢的全面了解仍然难以捉摸。这项提议的总体目标是通过分子设计和开发在生物相关条件下有效检测或输送硫化氢和硫化氢的新分子支架来回答这些具体问题。从事这些努力的学生将在化学和生物日益扩大的界面上接触到各种各样的主题和技术，因为他们打开了氧化还原信号社区的新前沿。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发有趣的互动化学讲座，以及积极招募代表人数不足的少数族裔大学生到维克森林大学从事研究工作。为了促进对硫化氢和硫化氢的流行率和生理意义的新研究，该项目旨在设计新的化学工具，以帮助在生物相关的条件下输送或检测这两种气体。具体地说，将采用全新的化学方法，通过分析物引发的环化反应，选择性地从含硫基序中释放硫化氢。这一独特的机制途径将被用来解锁一类捐赠者，这些捐赠者有可能通过靶向特定组织和细胞器的能力来推动硫化物信号研究领域的发展；选择性地对疾病中上调的刺激做出反应；以及自我报告他们通过并发荧光团组装实时传递硫化氢。该项目还代表了一项开创性的努力，以产生新的供体和针对硫化氢的基于反应的探针。鉴于此类化合物的稀缺性，这种新的化学有可能加速分子信号研究，并引发一个新兴的科学领域，旨在探索硫化氢的化学生物学和固有的生理功能，包括其促进氧化翻译后修饰的倾向。该奖项反映了NSF的法定使命，并通过使用基金会的智力优势和更广泛的影响审查标准进行评估，被认为值得支持。

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.