Executive Summary : | The cellular sulfane sulfur pool, derived from hydrogen sulfide and related sulfur species, has emerged as a crucial physiological antioxidant reservoir. These species respond to oxidative stress and protect cells from the harmful effects of reactive oxygen species (ROS). Decreased levels of sulfane sulfur species have been linked to various diseases and pathological conditions, impacting health and well-being. The subcellular location of sulfane sulfur, mitochondrial versus cytosolic, may also play a role in its ability to counteract oxidative stress and contribute to cellular health. Small molecules that modulate sulfane sulfur levels are being developed as antioxidants and anti-inflammatory compounds, potentially contributing positively to cellular health and longevity. The researchers propose using the cell's biosynthetic pathways for sulfane sulfur generation to modulate these species. They propose designing artificial substrates for enzymes involved in the biosynthesis of sulfane sulfur, such as 3-Mercaptopyruvate sulfurtransferase (3-MST), which is widely expressed and has been implicated in compromised oxidative stress response. The researchers found that artificial substrates for this enzyme could enhance sulfane sulfur and protect cells from oxidative stress. The researchers plan to use computational models and experimental data to optimize structures with sulfane sulfur generating ability and evaluate their potential to protect cells from oxidative stress and inflammation. They also plan to prepare prodrug forms for these substrates to facilitate selective delivery of sulfane sulfur species to specific cell types. The proposal aims to establish a strong foundation for small organic molecules that can reliably and predictably enhance cellular sulfane sulfur and exploit their therapeutic potential. |