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Characterization of the DNA and Membrane Interactions of a Bioreducible Cell-Penetrating Foldamer in its Monomeric and Dimeric Form
journal contribution
posted on 2020-05-22, 21:04 authored by Christopher Aisenbrey, Céline Douat, Antoine Kichler, Gilles Guichard, Burkhard BechingerThe
biophysical properties of a designed bioreducible oligourea
foldamer, which shows excellent transfection activities in its dimeric
form are presented. Binding isotherms of the monomer as well as of
the dimer to both DNA and lipid membranes were determined by indole
fluorescence. Comparing the monomer with the dimer allows both a precise
biophysical characterization of the role of dimerization and characterization
of how the covalent linkage between two monomers affects the transfection
activity. The results indicate that dimerization results in pronounced
changes in the thermodynamics of different steps of the transfection
process, which extend well beyond simple steric effects within the
dimer. A model emerges where the imidazole-containing polymers compact
DNA at neutral pH, but they liberate the polyurea from the DNA complex
at low pH, thus being able to rupture acidified endosomes. Indeed,
the dimerization inverts the pH dependence of the binding affinities
toward the requirements suggested by this model for efficient transfection.
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binding affinitiesdimerization invertscharacterizationdimeric formpH dependencedimerization resultstransfection activityindole fluorescencemonomersteric effectsDNAimidazole-containing polymerstransfection processcovalent linkageDimeric FormBinding isothermsmodellipid membranestransfection activitiesMembrane InteractionsBioreducible Cell-Penetrating Foldamerbioreducible oligourea foldamer
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