Pharmacological Regulation of the H₂S and Inhibitors

Hydrogen sulfide (H₂S) is an endogenous gaseous molecule that regulates physiologic and pathophysiological processes in various cells and tissues. H₂S levels are decreased in diabetes mellitus, ischemia, and aging, and increased in inflammation and cancer. Various donors with diverse H₂S release profiles include oxidant-triggered donors, pH-dependent donors, esterase-activated donors, and mitochondrial-targeted compounds. Clinically approved nonsteroidal anti-inflammatory drugs are also coupled with H₂S-donating groups; ATB-346, an H₂S-donating derivative of naproxen, is one such compound in clinical trials. Pharmacological inhibitors of H₂S synthesis include small molecule compounds targeting each of the three H₂S-producing enzymes—cystathionine-β-synthase (CBS), cystathionine-γ-lyase, and 3-mercaptopyruvate sulfurtransferase. Cell-permeable prodrugs of the CBS inhibitors, aminooxyacetate or benserazide, may serve as starting points for future clinical development. In this paper, we review H₂S donors and H₂S biosynthesis inhibitors in light of their modes of action, biological effects, and potential therapeutic utility.