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 solubilized and 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 hydrophobic motifs, such as 2-hydroxypropyl β-cyclodextrin (2HPβ), are sufficient solubilize S 8 at concentrations up to 2.0 ± 0.2 mM in aqueous solution. We demonstrate that the solubilized S 8 is chemically accessible, can be reduced with 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 reaction of 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 reduces 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.