title: Design of a disulfide-less, pharmacologically inert, and chemically competent analog of maurocalcine for the efficient transport of impermeant compounds into cells.
abstract: Maurocalcine is a 33-mer peptide initially isolated from the venom of a Tunisian scorpion. It has proved itself valuable as a pharmacological activator of the ryanodine receptor and has helped the understanding of the molecular basis underlying excitation-contraction coupling in skeletal muscles. Because of its positively charged nature, it is also an innovative vector for the cell penetration of various compounds. We report a novel maurocalcine analog with improved properties: (i) the complete loss of pharmacological activity, (ii) preservation of the potent ability to carry cargo molecules into cells, and (iii) coupling chemistries not affected by the presence of internal cysteine residues of maurocalcine. We did this by replacing the six internal cysteine residues of maurocalcine by isosteric 2-aminobutyric acid residues and by adding an additional N-terminal biotinylated lysine (for a proof of concept analog) or an N-terminal cysteine residue (for a chemically competent coupling analogue). Additional replacement of a glutamate residue by alanyl at position 12 further improves the potency of these analogues. Coupling to several cargo molecules or nanoparticles are presented to illustrate the cell penetration potency and usefulness of these pharmacologically inactive analogs.
authors.affiliation: Research Group 3 Calcium Channels, Functions, and Pathologies, Unité Inserm 836, Grenoble Institute of Neuroscience, Université Joseph Fourier, Site Santé, BP 170, 38042 Grenoble Cedex 09, France.
authors.forename: Narendra
authors.initials: N
authors.lastname: Ram
authors.forename: Norbert
authors.initials: N
authors.lastname: Weiss
authors.forename: Isabelle
authors.initials: I
authors.lastname: Texier-Nogues
authors.forename: Sonia
authors.initials: S
authors.lastname: Aroui
authors.forename: Nicolas
authors.initials: N
authors.lastname: Andreotti
authors.forename: Fabienne
authors.initials: F
authors.lastname: Pirollet
authors.forename: Michel
authors.initials: M
authors.lastname: Ronjat
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Sabatier
authors.forename: Hervé
authors.initials: H
authors.lastname: Darbon
authors.forename: Vincent
authors.initials: V
authors.lastname: Jacquemond
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
mesh_terms: D000818:Animals; D016466:CHO Cells; D006224:Cricetinae; D003412:Cricetulus; D004220:Disulfides / Q000737:chemistry; D004337:Drug Carriers / Q000138:chemical synthesis / Q000737:chemistry / Q000494:pharmacology*; D006801:Humans; D051379:Mice; D018482:Muscle, Skeletal / Q000166:cytology / Q000378:metabolism; D012604:Scorpion Venoms / Q000138:chemical synthesis / Q000235:genetics / Q000494:pharmacology*; D012605:Scorpions / Q000235:genetics / Q000378:metabolism
chemical_list: D004220:Disulfides; D004337:Drug Carriers; D012604:Scorpion Venoms; C406406:maurocalcine