ChemBioChem doi:10.1002/cbic.201402312

Hydrogen sulfide (H2S) is thought to exert its biological effects through the S-sulfhydration of biological molecules, such as cysteine side chains, forming persulfides. However, studying this important modification has been challenging owing to the intrinsic reactivity of persulfides. Additionally, existing synthetic methods to generate persulfides use H2S in reactions that typically do not proceed to completion, making it difficult to conclusively determine that biological outcomes are linked to the presence of the persulfide rather than H2S. To assist in these efforts, Artaud and Galardon envisioned a new route to make persulfides. It has been shown that acyl-protected disulfides can be converted to persulfides and that this process can be influenced by the presence of amines. The authors build on this chemistry in their design of a stable precursor molecule, P*, which contains a protected disulfide adjacent to an amine that can, when deprotonated, participate in an intermolecular acyl transfer to generate an acylated amine and persulfide group (shown). The acyl transfer occurs on a rapid timescale at near-neutral pH without evolving H2S. The authors successfully apply their new reagent in two cases known to involve persulfides: the sulfhydration of 8-NO2-cGMP and the reduction of cytochrome c. P* can be made in a single synthetic step and is stable in solid form, enabling further applications of this new tool in chemical biology research.