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Design and Evaluation of Histidine-Rich Amphipathic Peptides for siRNA Delivery

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ABSTRACT

Purpose

Short linear peptides have a high potential for delivering various drugs with therapeutic potential, including nucleic acids. Recently, we have shown that the cationic amphipathic histidine-rich peptide LAH4 (KKALLALALHHLAHLALHLALALKKA) possesses high plasmid DNA delivery capacities. Since such peptides are thought to efficiently disrupt endosomal membranes, we have tested their ability to deliver small interfering RNA (siRNA) into mammalian cells.

Methods

Using a human cell line stably transfected with a luciferase-encoding expression vector, we have evaluated the ability of LAH4 and five derivatives thereof to deliver siRNAs and silence gene expression.

Results

The six peptides are all efficient siRNA delivery vehicles whose efficiency in mediating gene silencing in 911-Luc cells was greater than that of commercially available compounds including Lipofectamine, DOTAP and polyethylenimine. In addition, by using the proton pump inhibitor bafilomycin A1, we show that efficient siRNA delivery to the cytosol requires acidification of the endosomes.

Conclusions

The LAH4 histidine-rich cationic amphipathic peptides represent an interesting and promising family of compounds for siRNA delivery.

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ACKNOWLEDGEMENT

This work was performed with the financial support of Vaincre la Mucoviscidose (VLM), the Association Française contre les Myopathies (AFM), ANR Transpep (PCV07_186700) and the Wellcome Trust (VIP award to AJM).

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Authors and Affiliations

  1. Genethon, 1bis rue de l’Internationale, BP60, 91002, Evry, France

    Bérangère Langlet-Bertin, Christian Leborgne & Antoine Kichler

  2. UMR 8151 CNRS-U1022 INSERM, Université René Descartes, Chimie Paristech, Paris, France

    Daniel Scherman & Antoine Kichler

  3. Faculté de Chimie, Institut Le Bel, 4 rue Blaise Pascal, 67000, Strasbourg, France

    Burkhard Bechinger & A. James Mason

  4. Pharmaceutical Science Division, King’s College London, 150 Stamford Street, London, UK

    A. James Mason

Authors
  1. Bérangère Langlet-Bertin
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  2. Christian Leborgne
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  3. Daniel Scherman
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  4. Burkhard Bechinger
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  5. A. James Mason
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  6. Antoine Kichler
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Correspondence to Antoine Kichler.

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Langlet-Bertin, B., Leborgne, C., Scherman, D. et al. Design and Evaluation of Histidine-Rich Amphipathic Peptides for siRNA Delivery. Pharm Res 27, 1426–1436 (2010). https://doi.org/10.1007/s11095-010-0138-2

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  • DOI: https://doi.org/10.1007/s11095-010-0138-2

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