Fragment-based de novo design of a cystathionine γ-lyase selective inhibitor blocking hydrogen sulfide production

摘要

Hydrogen sulfide is an essential catabolite that intervenes in the pathophysiol. of several diseases from hypertension to stroke, diabetes and pancreatitis. It is endogenously synthesized mainly by two pyridoxal-​5'-​phosphate-​dependent enzymes involved in L-​cysteine metab.: cystathionine-​ss-​synthase (CBS) and cystathionine-​γ-​lyase (CSE)​. Research in this field is currently impaired by the lack of pharmacol. tools such as selective enzymic inhibitors that could target specifically only one of these pathways. We used a novel approach based on a hybrid method that includes drug design, synthetic biol., metabolomics and pharmacol. assays to rationally design a new inhibitor selective for the CSE enzyme. The identification of this compd. opens new frontiers towards a better understanding of the role of CSE over CBS in the pathophysiol. of diseases where a role for the H2S pathway has been proposed and the development of new lead compds. that could target the CSE enzyme.