Pharmacological Regulation of the H2S and Inhibitors

Abstract

Hydrogen sulfide (H2S) is an endogenous gaseous molecule that regulates physiologic and pathophysiologicalprocesses in various cells and tissues. H2S levels are decreased in diabetes mellitus, ischemia, and aging, and increased ininflammation and cancer. Various donors with diverse H2S release profiles include oxidant-triggered donors, pH-dependentdonors, esterase-activated donors, and mitochondrial-targeted compounds. Clinically approved nonsteroidal anti-inflammatorydrugs are also coupled with H2S-donating groups; ATB-346, an H2S-donating derivative of naproxen, is one suchcompound in clinical trials. Pharmacological inhibitors of H2S synthesis include small molecule compounds targeting eachof 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 startingpoints for future clinical development. In this paper, we review H2S donors and H2S biosynthesis inhibitors in light of theirmodes of action, biological effects, and potential therapeutic utility.