title: Fragment-based de novo design of a cystathionine γ-lyase selective inhibitor blocking hydrogen sulfide production.
abstract: Hydrogen sulfide is an essential catabolite that intervenes in the pathophysiology 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 metabolism: cystathionine-ß-synthase (CBS) and cystathionine-γ-lyase (CSE). Research in this field is currently impaired by the lack of pharmacological tools such as selective enzymatic 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 biology, metabolomics and pharmacological assays to rationally design a new inhibitor selective for the CSE enzyme. The identification of this compound opens new frontiers towards a better understanding of the role of CSE over CBS in the pathophysiology of diseases where a role for the H2S pathway has been proposed and the development of new lead compounds that could target the CSE enzyme.
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.|Department of Neuroscience, Wohl Institute, King's College London, Denmark Hill Campus, London SE5, UK.
authors.forename: Angela
authors.initials: A
authors.lastname: Corvino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Beatrice
authors.initials: B
authors.lastname: Severino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Ferdinando
authors.initials: F
authors.lastname: Fiorino
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Francesco
authors.initials: F
authors.lastname: Frecentese
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Magli
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Elisa
authors.initials: E
authors.lastname: Perissutti
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Vincenzo
authors.initials: V
authors.lastname: Santagada
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Mariarosaria
authors.initials: M
authors.lastname: Bucci
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Cirino
authors.affiliation: MRC Biomedical NMR Centre, NIMR, NW7 1AA, London.
authors.forename: Geoff
authors.initials: G
authors.lastname: Kelly
authors.affiliation: Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Italy.
authors.forename: Luigi
authors.initials: L
authors.lastname: Servillo
authors.affiliation: Technical University of Munich, Garching Campus, Munich, Germany.
authors.forename: Grzegorz
authors.initials: G
authors.lastname: Popowicz
authors.affiliation: Department of Neuroscience, Wohl Institute, King's College London, Denmark Hill Campus, London SE5, UK.
authors.forename: Annalisa
authors.initials: A
authors.lastname: Pastore
authors.affiliation: Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
authors.forename: Giuseppe
authors.initials: G
authors.lastname: Caliendo
mesh_terms: D000818:Animals; D003542:Cystathionine gamma-Lyase / Q000037:antagonists & inhibitors* / Q000378:metabolism; D004791:Enzyme Inhibitors / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology; D006862:Hydrogen Sulfide / Q000378:metabolism*; D051379:Mice
chemical_list: D004791:Enzyme Inhibitors; D003542:Cystathionine gamma-Lyase; D006862:Hydrogen Sulfide