PL04 Modulation of inflammatory and vascular signalling by novel slow release and mitochondria-targeted H2S donors

Abstract

Hydrogen sulfide (H2S) is emerging as important mediator in disparate physiological and pathophysiological processes [1] . These studies have highlighted the therapeutic potential for the pharmacological manipulation of H2S. Indeed, H2S donor molecules such as GYY4137, ATB-346, SPRC and ATB-337 have been shown to regulate blood pressure in experimental induced hypertension and to inhibit tissue damage, oedema and inflammatory signalling in sepsis, colitis and arthritis and many of these studies will be reviewed elsewhere at this meeting. The development and characterisation of appropriate H2S donors such as these are crucial as commonly used sulfide salts such as NaSH or Na2S, generate H2S (and Na+) as an instantaneous bolus rather than model the slow and sustained enzymatic generation of H2S from CSE, CBS or 3-MST [1] , [2] . As with NO and CO, it is likely that the tissue and/or cellular responsiveness to H2S may well be dependent upon the manner in which cells/tissues are exposed to this gas [2] . However, pharmacological tools which generate H2S at different rates (analogous to the NONOates in the nitric oxide field) are currently unavailable. We have attempted to overcome this limitation and synthesised several novel compounds capable of generating H2S at different rates (e.g. AP67, AP72, AP105). These compounds will enable researchers to characterise the physiology and pharmacology of H2S in a variety of physiological and pathophysiological models. More recently we have synthesised novel dithiolethione (e.g. AP39) or thiohydroxybenzamide (e.g. AP123) derivatives containing a triphenylphosphonium moiety enabling specific delivery of sub-nanomolar concentrations of the compounds to mitochondria. The anti-hypertensive, anti-inflammatory, cytoprotective and anti-proliferative effects in vitro, ex vivo and in vivo of these compounds in comparison to other H2S donors will be discussed. These studies highlight the potential for H2S manipulation and mitochondrial delivery of H2S to regulate vascular and inflammatory signalling in health and disease.