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

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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.