A Review of Chemical Tools for Studying Small Molecule Persulfides: Detection and Delivery

Hydrogen sulfide (H₂S) has gained significant attention as a potent bioregulator in the redox metabolome, but it is just one of many reactive sulfur species (RSS). Recently, small molecule persulfides (structure RSSH) have emerged as RSS of particular interest due to their enhanced antioxidant abilities compared to H₂S and their ability to directly convert protein thiols into protein persulfides, suggesting that persulfides may have distinct physiological functions from H₂S. However, persulfides exhibit instability and cross-reactivity that hampers the elucidation of their precise biological roles. As such, chemists have designed chemical tools and techniques to facilitate the study of persulfides under various conditions. These molecules and methods include persulfide trapping reagents and sensors, as well as compounds that degrade in response to various triggers to release persulfides, termed persulfide donors. There now exist a variety of persulfide donor classes, some of which possess tissue-targeting capabilities designed to mimic localized endogenous production of RSS. This Review briefly covers the physicochemical properties of persulfides, the endogenous production of small molecule persulfides, and their reactions with protein thiols and other reactive species. These introductory sections are followed by a discussion of chemical tools used in persulfide chemical biology, with critical analysis of recent advancements in the field and commentary on potential directions for future research.