D-Maurocalcine, a pharmacologically inert efficient cell-penetrating peptide analogue

J Biol Chem. 2010 Oct 29;285(44):34168-80. doi: 10.1074/jbc.M110.104919. Epub 2010 Jul 7.

Abstract

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • CHO Cells
  • Calcium Channels / chemistry
  • Cell Membrane / metabolism
  • Circular Dichroism
  • Cricetinae
  • Cricetulus
  • Fluoresceins / chemistry
  • Magnetic Resonance Spectroscopy / methods
  • Microscopy, Confocal / methods
  • Peptide Hydrolases / chemistry
  • Peptides / chemistry*
  • Ryanodine / chemistry
  • Scorpion Venoms / chemistry*
  • Scorpion Venoms / pharmacology
  • Tetrazolium Salts / pharmacology
  • Thiazoles / pharmacology

Substances

  • Calcium Channels
  • Fluoresceins
  • Peptides
  • Scorpion Venoms
  • Tetrazolium Salts
  • Thiazoles
  • maurocalcine
  • Ryanodine
  • 6-carboxyfluorescein
  • Peptide Hydrolases
  • thiazolyl blue

Associated data

  • PDB/2KQL