Spontaneous membrane-translocating peptides: influence of peptide self-aggregation and cargo polarity

Peptides that translocate spontaneously across cell membranes could transform the field of drug delivery by enabling the transport of otherwise membrane-impermeant molecules into cells. In this regard, a 9-aminoacid-long motif (representative sequence: PLIYLRLLR , hereafter Translocating Motif 9, TM...

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Bibliographic Details
Published in:Scientific reports 2015-11, Vol.5 (1), p.16914, Article 16914
Main Authors: Macchi, Sara, Signore, Giovanni, Boccardi, Claudia, Di Rienzo, Carmine, Beltram, Fabio, Cardarelli, Francesco
Format: Article
Language:English
Subjects:
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Aggregates
Amino Acid Sequence
Animals
Cell Membrane - metabolism
Cell membranes
Cell-Penetrating Peptides - chemical synthesis
Cell-Penetrating Peptides - chemistry
Cell-Penetrating Peptides - metabolism
CHO Cells
Cricetinae
Cricetulus
Diffusion
Drug Carriers - chemistry
Drug delivery
Dynamic Light Scattering
Fluorescence spectroscopy
Fluorescent Dyes - chemistry
High-throughput screening
Humanities and Social Sciences
Membranes
Micelles
Microscopy
Microscopy, Confocal
multidisciplinary
Mutagenesis
Nanoparticles - chemistry
Peptides
Plasma
Polarity
Science
Self
Translocation
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Summary:Peptides that translocate spontaneously across cell membranes could transform the field of drug delivery by enabling the transport of otherwise membrane-impermeant molecules into cells. In this regard, a 9-aminoacid-long motif (representative sequence: PLIYLRLLR , hereafter Translocating Motif 9, TM9) that spontaneously translocates across membranes while carrying a polar dye was recently identified by high-throughput screening. Here we investigate its transport properties by a combination of in cuvette physico-chemical assays, rational mutagenesis, live-cell confocal imaging and fluorescence correlation spectroscopy measurements. We unveil TM9 ability to self-aggregate in a concentration-dependent manner and demonstrate that peptide self-aggregation is a necessary –yet not sufficient– step for effective membrane translocation. Furthermore we show that membrane crossing can occur with apolar payloads while it is completely inhibited by polar ones. These findings are discussed and compared to previous reports. The present results impose a careful rethinking of this class of sequences as direct-translocation vectors suitable for delivery purposes.
ISSN:2045-2322
2045-2322
DOI:10.1038/srep16914