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Stereoselective pH Responsive Peptide Dendrimers for siRNA Transfection

Type of publication Peer-reviewed
Publikationsform Original article (peer-reviewed)
Author Heitz Marc, Javor Sacha, Darbre Tamis, Reymond Jean-Louis,
Project Chemical Space Design of Small Molecules and Peptides
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Original article (peer-reviewed)

Journal Bioconjugate Chemistry
Volume (Issue) 30(8)
Page(s) 2165 - 2182
Title of proceedings Bioconjugate Chemistry
DOI 10.1021/acs.bioconjchem.9b00403


Transfecting nucleic acids into cells is an essential procedure in biological research usually performed using nonviral transfection reagents. Unfortunately, most transfection reagents have polymeric or undisclosed structures and require nonstandard synthetic procedures. Herein we report peptide dendrimers accessible as pure products from standard building blocks by solid-phase peptide synthesis and acting as nontoxic single component siRNA transfection reagents for a variety of cell lines with equal or better performance than the gold standard lipofectamine L2000. Structure–activity relationships and mechanistic studies illuminate their transfection mechanism in unprecedented detail. Stereoselective dendrimer aggregation via intermolecular β-sheets at neutral pH enables siRNA complexation to form nanoparticles which enter cells by endocytosis. Endosome acidification triggers protonation of amino termini and rearrangement to an α-helical conformation forming smaller dendrimer/siRNA nanoparticles, which escape the endosome and release their siRNA cargo in the cytosol. Two particularly efficient d-enantiomeric dendrimers are proposed as new reference reagents for siRNA transfection.