d-Maurocalcine, a Pharmacologically Inert Efficient Cell-penetrating Peptide Analogue

Maurocalcine has been the first demonstrated animal toxin acting as a cell-penetrating peptide. Although it possesses competitive advantages, its use as a cell-penetrating peptide (CPP) requires that analogues be developed that lack its characteristic pharmacological activity on ryanodine-sensitive...

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Bibliographic Details
Published in:The Journal of biological chemistry 2010-10, Vol.285 (44), p.34168-34180
Main Authors: Poillot, Cathy, Dridi, Kaouthar, Bichraoui, Hicham, Pêcher, Julien, Alphonse, Sebastien, Douzi, Badreddine, Ronjat, Michel, Darbon, Hervé, De Waard, Michel
Format: Article
Language:English
Subjects:
Animals
Calcium Channels - chemistry
Cell Membrane - metabolism
CHO Cells
Circular Dichroism
Circular Dichroism (CD)
Cricetinae
Cricetulus
Fluoresceins - chemistry
Fluorescence
Magnetic Resonance Spectroscopy - methods
Membrane Biology
Membrane Trafficking
Microscopy, Confocal - methods
NMR
Peptide Chemical Synthesis
Peptide Hydrolases - chemistry
Peptides - chemistry
Plasma Membrane
Protein Folding
Protein Structure
Protein Structure and Folding
Ryanodine
Ryanodine - chemistry
Scorpion Venoms - chemistry
Scorpion Venoms - pharmacology
Tetrazolium Salts - pharmacology
Thiazoles - pharmacology
Toxins
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Summary:Maurocalcine has been the first demonstrated animal toxin acting as a cell-penetrating peptide. Although it possesses competitive advantages, its use as a cell-penetrating peptide (CPP) requires that analogues be developed that lack its characteristic pharmacological activity on ryanodine-sensitive calcium channels without affecting its cell-penetrating and vector efficiencies. Here, we present the synthesis, three-dimensional 1H NMR structure, and activity of d-maurocalcine. We demonstrate that it possesses all of the desired features for an excellent CPP: preserved structure, lack of pharmacological action, conserved vector properties, and absence of cell toxicity. This is the first report of a folded/oxidized animal toxin in its d-diastereomer conformation for use as a CPP. The protease resistance of this new peptide analogue, combined with its efficient cell penetration at concentrations devoid of cell toxicity, suggests that d-maurocalcine should be an excellent vector for in vivo applications.
ISSN:0021-9258
1083-351X
DOI:10.1074/jbc.M110.104919