Stereoselective pH Responsive Peptide Dendrimers for siRNA Transfection

Heitz, Marc; Javor, Sacha; Darbre, Tamis; Reymond, Jean-Louis (2019). Stereoselective pH Responsive Peptide Dendrimers for siRNA Transfection. Bioconjugate chemistry, 30(8), pp. 2165-2182. American Chemical Society 10.1021/acs.bioconjchem.9b00403

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

08 Faculty of Science > Departement of Chemistry and Biochemistry

UniBE Contributor:

Heitz, Marc; Javor, Sacha; Darbre, Tamis and Reymond, Jean-Louis

Subjects:

500 Science > 570 Life sciences; biology
500 Science > 540 Chemistry

ISSN:

1043-1802

Publisher:

American Chemical Society

Language:

English

Submitter:

Sandra Tanja Zbinden Di Biase

Date Deposited:

24 Jan 2020 13:44

Last Modified:

24 Jan 2020 13:44

Publisher DOI:

10.1021/acs.bioconjchem.9b00403

PubMed ID:

31398014

BORIS DOI:

10.7892/boris.138512

URI:

https://boris.unibe.ch/id/eprint/138512

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