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Rational design of a fluorescent NADPH derivative imaging constitutive nitric-oxide synthases upon two-photon excitation.

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Li, Yun Wang, Huan Tarus, Bogdan Romero Perez, Miguel [UCL] Morellato, Laurence Dessy, Chantal [UCL] Slama-Schwok, Anny

We report the structure-based design and synthesis of a unique NOS inhibitor, called nanoshutter NS1, with two-photon absorption properties. NS1 targets the NADPH site of NOS by a nucleotide moiety mimicking NADPH linked to a conjugated push-pull chromophore with nonlinear absorption properties. Because NS1 could not provide reducing equivalents to the protein and competed with NADPH binding, it efficiently inhibited NOS catalysis. NS1 became fluorescent once bound to NOS with an excellent signal-to-noise ratio because of two-photon excitation avoiding interference from the flavin-autofluorescence and because free NS1 was not fluorescent in aqueous solutions. NS1 fluorescence enhancement was selective for constitutive NOS in vitro, in particular for endothelial NOS (eNOS). Molecular dynamics simulations suggested that two variable residues among NOS isoforms induced differences in binding of NS1 and in local solvation around NS1 nitro group, consistent with changes of NS1 fluorescence yield. NS1 colocalized with eNOS in living human umbilical vein endothelial cells. Thus, NS1 constitutes a unique class of eNOS probe with two-photon excitation in the 800-950-nm range, with great perspectives for eNOS imaging in living tissues.

Document type Article de périodique (Journal article)
Access type Accès libre
Publication date 2012
Language Anglais
Journal information "Proceedings of the National academy of sciences of the United States of America" - Vol. 109, no. 31, p. 12526-12531 (2012)
Peer reviewed yes
Publisher National academy of sciences ((United States) [S.l.])
issn 0027-8424
e-issn 1091-6490
Publication status Publié
Affiliations UCL - SSS/IREC - Institut de recherche expérimentale et clinique
UCL - SSS/IREC/FATH - Pôle de Pharmacologie et thérapeutique
MESH Subject Catalysis ; Nitric Oxide Synthase Type III ; Fluorescent Dyes ; Human Umbilical Vein Endothelial Cells ; Humans ; Isoenzymes ; Microscopy, Fluorescence, Multiphoton ; Molecular Dynamics Simulation ; NADP ; Nitric Oxide
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Bibliographic reference Li, Yun ; Wang, Huan ; Tarus, Bogdan ; Romero Perez, Miguel ; Morellato, Laurence ; et. al. Rational design of a fluorescent NADPH derivative imaging constitutive nitric-oxide synthases upon two-photon excitation.. In: Proceedings of the National academy of sciences of the United States of America, Vol. 109, no. 31, p. 12526-12531 (2012)
Permanent URL http://hdl.handle.net/2078/116248