Toward Direct Protein S-Persulfidation: A Prodrug Approach That Directly Delivers Hydrogen Persulfide

A general strategy of delivering hydrogen persulfide (H2S2) is described herein. Esterase- and phosphatase-sensitive H2S2 prodrugs with tunable release rates have been synthesized. Their utility is validated in examining protein S-persulfidation. With this unique approach of directly delivering H2S2, our findings reaffirmed that S-persulfidation leads to decreased activity of glyceraldehyde 3-phosphate dehydrogenase. This new approach complements available prodrugs/donors that directly deliver a single species, including hydrogen sulfide, perthiol, and COS, and will be very useful as part of the toolbox for delineating the mechanisms of sulfur signaling.