2. Academic Validation
  3. Fragment-based de novo design of a cystathionine γ-lyase selective inhibitor blocking hydrogen sulfide production

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

  • Sci Rep. 2016 Oct 6;6:34398. doi: 10.1038/srep34398.
Angela Corvino 1 2,  Beatrice Severino 1,  Ferdinando Fiorino 1,  Francesco Frecentese 1,  Elisa Magli 1,  Elisa Perissutti 1,  Vincenzo Santagada 1,  Mariarosaria Bucci 1,  Giuseppe Cirino 1,  Geoff Kelly 3,  Luigi Servillo 4,  Grzegorz Popowicz 5,  Annalisa Pastore 2,  Giuseppe Caliendo 1
Affiliations

Affiliations

  • 1 Department of Pharmacy, University of Naples "Federico II" - Via D. Montesano, 49, 80131-Napoli, Italy.
  • 2 Department of Neuroscience, Wohl Institute, King's College London, Denmark Hill Campus, London SE5, UK.
  • 3 MRC Biomedical NMR Centre, NIMR, NW7 1AA, London.
  • 4 Department of Biochemistry, Biophysics and General Pathology, Second University of Naples, Italy.
  • 5 Technical University of Munich, Garching Campus, Munich, Germany.
PMID: 27708394 DOI: 10.1038/srep34398
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.

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