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Luciferase-induced photoreductive uncaging of small-molecule effectors

Eric Lindberg, Simona Angerani, Marcello Anzola and Nicolas Winssinger ()
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Eric Lindberg: University of Geneva
Simona Angerani: University of Geneva
Marcello Anzola: University of Geneva
Nicolas Winssinger: University of Geneva

Nature Communications, 2018, vol. 9, issue 1, 1-9

Abstract: Abstract Bioluminescence resonance energy transfer (BRET) is extensively used to study dynamic systems and has been utilized in sensors for studying protein proximity, metabolites, and drug concentrations. Herein, we demonstrate that BRET can activate a ruthenium-based photocatalyst which performs bioorthogonal reactions. BRET from luciferase to the ruthenium photocatalyst is used to uncage effector molecules with up to 64 turnovers of the catalyst, achieving concentrations >0.6 μM effector with 10 nM luciferase construct. Using a BRET sensor, we further demonstrate that the catalysis can be modulated in response to an analyte, analogous to allosterically controlled enzymes. The BRET-induced reaction is used to uncage small-molecule drugs (ibrutinib and duocarmycin) at biologically effective concentrations in cellulo.

Date: 2018
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DOI: 10.1038/s41467-018-05916-9

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