Zhu_2024_ACS.Chem.Biol__

Hydrogen sulfide (H(2)S) has emerged as a significant biomolecule with diverse activities, akin to other gaseous signaling molecules such as nitric oxide (NO) and carbon monoxide (CO). In the present study, we report on the development of esterase-activated donors that track their direct cellular donation of H(2)S by enlisting a cyclization reaction onto a thioamide that forms a fluorogenic byproduct. This simple donor design provides a noninvasive method for monitoring the biological delivery and activity of H(2)S, along with access to a library of compounds with highly variable rates of H(2)S delivery. These studies culminated with the identification of a slow-release, yet highly efficient, donor (ZL-DMA-Ph) that was shown to self-report its gradual and continuous cellular donation of H(2)S for up to 24 h which, in addition to better mimicking the natural biosynthesis of H(2)S, provided impressive cytoprotection in a cellular cardiotoxicity model, even at submicromolar concentrations. In total, these findings indicate that the esterase-triggered fluorogenic donors identified in this study will offer new opportunities for exploring the chemical biology and therapeutic potential of exogenous H(2)S supplementation.