Modified cyclodextrins solubilize elemental sulfur in water and enable biological sulfane sulfur delivery

An important form of biological sulfur is sulfane sulfur, or S 0 , which is found in polysulfide and persulfide compounds as well as in elemental sulfur. Sulfane sulfur, often in the form of S 8 , functions as a key energy source in the metabolic processes of thermophilic Archaean organisms found in sulfur-rich environments and can be metabolized both aerobically and anaerobically by different archaeons. Despite this importance, S 8 has a low solubility in water (∼19 nM), raising questions of how it can be made chemically accessible in complex environments. Motivated by prior crystallographic data showing S 8 binding to hydrophobic motifs in filamentous glycoproteins from the sulfur reducing Staphylothermus marinus anaerobe, we demonstrate that simple macrocyclic hydrophobic motifs, such as 2-hydroxypropyl β-cyclodextrin (2HPβ), are sufficient to solubilize S 8 at concentrations up to 2.0 ± 0.2 mM in aqueous solution. We demonstrate that the solubilized S 8 can be reduced with the common reductant tris (2-carboxyethyl)phosphine (TCEP) and reacts with thiols to generate H 2 S. The thiol-mediated conversion of 2HPβ/S 8 to H 2 S ranges from 80% to quantitative efficiency for Cys and glutathione (GSH). Moreover, we demonstrate that 2HPβ can catalyze the Cys-mediated reduction of S 8 to H 2 S in water. Adding to the biological relevance of the developed systems, we demonstrate that treatment of Raw 264.7 macrophage cells with the 2HPβ/S 8 complex prior to LPS stimulation decreases NO 2 − levels, which is consistent with known activities of bioavailable H 2 S and sulfane sulfur. Taken together, these investigations provide a new strategy for delivering H 2 S and sulfane sulfur in complex systems and more importantly provide new insights into the chemical accessibility and storage of S 0 and S 8 in biological environments. Sulfane sulfur, or S 0 , is found in polysulfide and persulfide compounds in biology. We demonstrate that modified cyclodextrins can solubilize S 8 in water, increase its reactivity with biological nucleophiles, and enable delivery to live cells.