Fragment-based de novo design of a cystathionine γ-lyase selective inhibitor blocking hydrogen sulfide production
Angela Corvino
Beatrice Severino
Ferdinando Fiorino
Francesco Frecentese
Elisa Magli
Elisa Perissutti
Vincenzo Santagada
Mariarosaria Bucci
Giuseppe Cirino
Geoff Kelly
Luigi Servillo
Grzegorz Popowicz
Annalisa Pastore
Giuseppe Caliendo
10779/crick.12656729.v1
https://crick.figshare.com/articles/journal_contribution/Fragment-based_de_novo_design_of_a_cystathionine_-lyase_selective_inhibitor_blocking_hydrogen_sulfide_production/12656729
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.
2020-07-17 16:26:30
Animals
Cystathionine gamma-Lyase
Enzyme Inhibitors
Hydrogen Sulfide
Mice
NMR
0601 Biochemistry and Cell Biology
0299 Other Physical Sciences