International Union of Basic and Clinical Pharmacology. CII: Pharmacological Modulation of H2S Levels: H2S Donors and H2S Biosynthesis Inhibitors

Over the last decade, hydrogen sulfide (H₂S) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, H₂S is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. H₂S levels are decreased in a number of conditions (e.g., diabetes mellitus, ischemia, and aging) and are increased in other states (e.g., inflammation, critical illness, and cancer). Over the last decades, multiple approaches have been identified for the therapeutic exploitation of H₂S, either based on H₂S donation or inhibition of H₂S biosynthesis. H₂S donation can be achieved through the inhalation of H₂S gas and/or the parenteral or enteral administration of so-called fast-releasing H₂S donors (salts of H₂S such as NaHS and Na₂S) or slow-releasing H₂S donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated H₂S release profiles, including oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and organelle-targeted (e.g., mitochondrial) compounds. There are also approaches where existing, clinically approved drugs of various classes (e.g., nonsteroidal anti-inflammatories) are coupled with H₂S-donating groups (the most advanced compound in clinical trials is ATB-346, an H₂S-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of H₂S synthesis, there are now several small molecule compounds targeting each of the three H₂S-producing enzymes cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Although many of these compounds have their limitations (potency, selectivity), these molecules, especially in combination with genetic approaches, can be instrumental for the delineation of the biologic processes involving endogenous H₂S production. Moreover, some of these compounds (e.g., cell-permeable prodrugs of the CBS inhibitor aminooxyacetate, or benserazide, a potentially repurposable CBS inhibitor) may serve as starting points for future clinical translation. The present article overviews the currently known H₂S donors and H₂S biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.