EP03 Therapeutic outlook for hydrogen sulfide donors

Abstract

Considerable evidence has accumulated in recent years suggesting that H 2 S, synthesised from l -cysteine via cystathionine γ lyase (CSE) or cystathionine β synthase (CBS) or from 3-mercaptopyruvate via 3-mercaptopyruvate transferase (3-MST), plays a significant part in a range of physiological and/or pathophysiological processes. The possibility that either manipulating endogenous H 2 S biosynthesis or using H 2 S donor drugs may lead to new therapeutic entities was raised several years ago (e.g. [1] ). Increasingly, H 2 S is being thought of as a cytoprotective agent which restores physiological function in diseased cells or organ systems and hence interest has centred on identifying novel H 2 S donors. To date, a number of H 2 S donors have been characterized. These include thiones such as 5-( p -hydroxyphenyl)-1,2-dithione-3-thione (ADT-OH), cysteine derivatives such as S-allylcysteine (SAC) and S-propargyl-cysteine (S-SPRC), GYY4137 (morpholin-4-ium 4 methoxyphenyl (morpholino) phosphinodithioate), H 2 S-releasing derivatives of non-steroidal anti-inflammatory drugs (NSAID) such as S-diclofenac and, recently, a nitric oxide (NO) and H 2 S-releasing derivative of aspirin. In addition, sulfide salts such as sodium hydrosulfide (NaHS) also release H 2 S. Other H 2 S-releasing drugs are no doubt in the pipeline. Potential applications of some or all of these compounds include such diverse conditions as hypertension, cardiac failure, ischemic reperfusion injury, acute and chronic inflammation, cancer and even to promote healthy aging. For example, GYY4137 reduces knee joint swelling in mice injected with Freund’s adjuvant [2] and is anti-tumor in the mouse [3] . Thus, H 2 S donors have shown early promise in a range of therapeutic areas. The further development of H 2 S donors presents a number of difficulties. For example, equating plasma concentration of released H 2 S from such donors with biological activity in an animal model (or in man) is problematic since, not only is H 2 S rapidly metabolized to an array of products, but current techniques to measure the concentration of this endogenous gas are likely insufficiently sensitive or selective. In addition, efficacy would be better correlated with H 2 S concentration at the site where the gas produces its biological effect (not plasma) which may be extracellular or even intracellular perhaps close to or in mitochondria. Further work is also needed to assess the cell permeability of H 2 S donors in order to determine whether they ‘carry’ H 2 S into cells thereby ‘loading’ the cell with the gas. This presentation will provide an overview of the potential for H 2 S donors in the clinic.