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

Over the last decade, hydrogen sulfide (HS) has emerged as an important endogenous gasotransmitter in mammalian cells and tissues. Similar to the previously characterized gasotransmitters nitric oxide and carbon monoxide, HS is produced by various enzymatic reactions and regulates a host of physiologic and pathophysiological processes in various cells and tissues. HS 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 HS, either based on HS donation or inhibition of HS biosynthesis. HS donation can be achieved through the inhalation of HS gas and/or the parenteral or enteral administration of so-called fast-releasing HS donors (salts of HS such as NaHS and NaS) or slow-releasing HS donors (GYY4137 being the prototypical compound used in hundreds of studies in vitro and in vivo). Recent work also identifies various donors with regulated HS 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 HS-donating groups (the most advanced compound in clinical trials is ATB-346, an HS-donating derivative of the non-steroidal anti-inflammatory compound naproxen). For pharmacological inhibition of HS synthesis, there are now several small molecule compounds targeting each of the three HS-producing enzymes cystathionine--synthase (CBS), cystathionine--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 HS 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 HS donors and HS biosynthesis inhibitors, delineates their mode of action, and offers examples for their biologic effects and potential therapeutic utility.