Hydrogen sulphide: novel opportunity for drug discovery

Hydrogen sulphide (H2S) is emerging as an important endogenous modulator, which exhibits the beneficial effects of nitric oxide (NO) on the cardiovascular (CV) system, without producing toxic metabolites. H2S is biosynthesized in mammalian tissues by cystathionine-beta-synthase and cystathionine-?-lyase. H2S exhibits the antioxidant properties of inorganic and organic sulphites, behaving as a scavenger of reactive oxygen species. There is also clear evidence that H2S triggers other important effects, mainly mediated by the activation of ATP-sensitive potassium channels (KATP). This mechanism accounts for the vasorelaxing and cardioprotective effects of H2S. Furthermore, H2S inhibits smooth muscle proliferation and platelet aggregation. In non-CV systems, H2S regulates the functions of the central nervous system, as well as respiratory, gastroenteric, and endocrine systems. Conversely, H2S deficiency contributes to the pathogenesis of hypertension. Likewise, impairment of H2S biosynthesis is involved in CV complications associated with diabetes mellitus. There is also evidence of a cross-talk between the H2S and the endothelial NO pathways. In particular, recent observations indicate a possible pathogenic link between deficiencies of H2S activity and the progress of endothelial dysfunction. These biological aspects of endogenous H2S have led several authors to look at this mediator as the new NO that has given attractive opportunities to develop innovative classes of drugs. In this review, the main biological actions of H2S are discussed. Moreover, some examples of H2S-donors are shown, as well as some hybrids, in which H2S-releasing moieties are added to well-known drugs, for improving their pharmacodynamic profile or reducing the potential for adverse effects, are reported.