Responsive and Targeted Modulation of Reactive Sulfur Species

/ABSTRACT Small gaseous molecules, such as hydrogen sulfide (H2S), carbon monoxide (CO), and nitric oxide (NO), are vital signaling molecules that regulate numerous physiological processes, including vascular biology, immune function, and stress responses. Broadening to other related small molecules, reactive sulfur species (RSS) comprise an interconnected network of H2S, persulfides, polysulfides, and related hybrids that are increasingly recognized for their roles in redox biology, signaling, and disease modulation. The rapid growth of established roles of both H2S and RSS in human health, as well as the molecular level appreciation for signaling pathways involving these molecules, has propelled the need to develop and deploy innovative chemical approaches to manipulate and understand H2S and RSS in biology. Motivated by these opportunities, our research program aims to develop responsive tools for modulating RSS in specific cellular environments and to elucidate fundamental knowledge of H2S/RSS biological chemistry. These efforts support both immediate research impacts and longer-term potential therapeutic applications. Building from these goals, our prior innovations, and key gaps relating to RSS in human health, this R35 proposal aims to develop transformative tools and strategies for advancing H2S/RSS chemical biology and redox signaling. Over the next five years, we propose to investigate targeted and responsive H2S donors to expand and refine the therapeutic window; develop new responsive platforms for delivering persistent persulfides with unique biological activities; deploy innovative and selective RSS scavengers; and investigate emerging opportunities related to the biological chemistry of carbonyl sulfide (COS). These efforts span from purpose- and mechanism-inspired design to applications in cellular and in vivo environments. Our integrated approach will directly address critical gaps in the field by advancing our understanding of RSS activity and by delivering next-generation tools to advance both fundamental research and future translational applications relevant to human health. Project Number: 1R35GM161495-01 | Fiscal Year: 2026 | NIH Institute/Center: National Institute of General Medical Sciences (NIGMS) | Principal Investigator: Michael Pluth | Institution: UNIVERSITY OF OREGON, EUGENE, OR | Award Amount: $398,464 | Activity Code: R35 | Study Section: Maximizing Investigators' Research Award - E Study Section[MRAE] View on NIH RePORTER: https://reporter.nih.gov/project-details/11259376