Distinction between 2′- and 3′-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration - CNRS - Centre national de la recherche scientifique Accéder directement au contenu
Article Dans Une Revue Antioxidants Année : 2021

Distinction between 2′- and 3′-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration

Raoul Manuel
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Sébastien Dilly
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Sylvain Daunay
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Elodie Pramil
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Alexandre Escargueil
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Nathalie Ferrand
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Israel Agranat
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Michèle Sabbah

Résumé

Specific inhibition of NADPH oxidases (NOX) and NO-synthases (NOS), two enzymes associated with redox stress in tumor cells, has aroused great pharmacological interest. Here, we show how these enzymes distinguish between isomeric 2'- and 3'-phosphate derivatives, a difference used to improve the specificity of inhibition by isolated 2'- and 3'-phosphate isomers of our NADPH analogue NS1. Both isomers become fluorescent upon binding to their target proteins as observed by in vitro assay and in vivo imaging. The 2'-phosphate isomer of NS1 exerted more pronounced effects on NOS and NOX-dependent physiological responses than the 3'-phosphate isomer did. Docking and molecular dynamics simulations explain this specificity at the level of the NADPH site of NOX and NOS, where conserved arginine residues distinguished between the 2'-phosphate over the 3'-phosphate group, in favor of the 2'-phosphate.
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Dates et versions

hal-03248720 , version 1 (03-06-2021)

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Raoul Manuel, Michelle de Souza Lima, Sébastien Dilly, Sylvain Daunay, Patricia Abbe, et al.. Distinction between 2′- and 3′-Phosphate Isomers of a Fluorescent NADPH Analogue Led to Strong Inhibition of Cancer Cells Migration. Antioxidants , 2021, 10 (5), pp.723. ⟨10.3390/antiox10050723⟩. ⟨hal-03248720⟩
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