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 calcium channels without affecting its cell-penetrating and vector efficiencies. Here, we present the synthesis, three-dimensional (1)H 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.
Poillot
Cathy
C
Grenoble Institute of Neuroscience, INSERM U836, Site Santé de la Tronche, Bâtiment Edmond J Safra, Chemin Fortuné Ferrini, BP170, 38042 Grenoble Cedex 9, France.
Dridi
Kaouthar
K
Bichraoui
Hicham
H
Pêcher
Julien
J
Alphonse
Sebastien
S
Douzi
Badreddine
B
Ronjat
Michel
M
Darbon
Hervé
H
De Waard
Michel
M
D000818:Animals; D016466:CHO Cells; D015220:Calcium Channels / Q000737:chemistry; D002462:Cell Membrane / Q000378:metabolism; D002942:Circular Dichroism; D006224:Cricetinae; D003412:Cricetulus; D005452:Fluoresceins / Q000737:chemistry; D009682:Magnetic Resonance Spectroscopy / Q000379:methods; D018613:Microscopy, Confocal / Q000379:methods; D010447:Peptide Hydrolases / Q000737:chemistry; D010455:Peptides / Q000737:chemistry*; D012433:Ryanodine / Q000737:chemistry; D012604:Scorpion Venoms / Q000737:chemistry* / Q000494:pharmacology; D013778:Tetrazolium Salts / Q000494:pharmacology; D013844:Thiazoles / Q000494:pharmacology
D015220:Calcium Channels; D005452:Fluoresceins; D010455:Peptides; D012604:Scorpion Venoms; D013778:Tetrazolium Salts; D013844:Thiazoles; C406406:maurocalcine; D012433:Ryanodine; C024098:6-carboxyfluorescein; D010447:Peptide Hydrolases; C022616:thiazolyl blue