The role of tryptophans on the cellular uptake and membrane interaction of arginine-rich cell penetrating peptides - Sorbonne Université Access content directly
Journal Articles Biochimica et Biophysica Acta:Biomembranes Year : 2014

The role of tryptophans on the cellular uptake and membrane interaction of arginine-rich cell penetrating peptides

Abstract

Cell-penetrating peptides (CPP) are able to efficiently transport cargos across cell membranes without being cytotoxic to cells, thus present a great potential in drug delivery and diagnosis. While the role of cationic residues in CPPs has been well studied, that of Trp is still not clear. Herein 7 peptide analogs of RW9 (RRWWRRWRR, an efficient CPP) were synthesized in which Trp were systematically replaced by Phe residues. Quantification of cellular uptake reveals that substitution of Trp by Phe strongly reduces the internalization of all peptides despite the fact that they strongly accumulate in the cell membrane. Cellular internalization and biophysical studies show that not only the number of Trp residues but also their positioning in the helix and the size of the hydrophobic face they form are important for their internalization efficacy, the highest uptake occurring for the analog with 3 Trp residues. Using CD and ATR-FTIR spectroscopy we observe that all peptides became structured in contact with lipids, mainly in α-helix. Intrinsic tryptophan fluorescence studies indicate that all peptides partition in the membrane in about the same manner (Kp ~ 105) and that they are located just below the lipid headgroups (~ 10 Å) with slightly different insertion depths for the different analogs. Plasmon waveguide resonance studies reveal a direct correlation between the number of Trp residues and the reversibility of the interaction following membrane washing. Thus a more interfacial location of the CPP renders the interaction with the membrane more adjustable and transitory enhancing its internalization ability.
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Dates and versions

hal-01087623 , version 1 (26-11-2014)

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Marie-Lise Jobin, Marine Blanchet, Sarah Henry, Stéphane Chaignepain, Claude Manigand, et al.. The role of tryptophans on the cellular uptake and membrane interaction of arginine-rich cell penetrating peptides. Biochimica et Biophysica Acta:Biomembranes, 2014, 1848 (2), pp.593-602. ⟨10.1016/j.bbamem.2014.11.013⟩. ⟨hal-01087623⟩
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