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Séminaire Chimie ED459

Peptide disulfide bond mimetics

Prof. Paul F. Alewood (Division of Chemistry and Structural Biology, Institute for Molecular Bioscience, University of Queensland, Brisbane, Australia)

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Le Jeudi 04 Octobre 2012 à 13h45
UM2, salle de cours SC-16.01

Many organisms including snakes, spiders, scorpions, cone snails, fish and some mammalian species have evolved venom as either a defence mechanism or a weapon for prey capture [1]. These venoms typically contain a complex cocktail of bioactive disulfide-rich small polypeptides which target a wide range of receptors including ion channels, GPCRs, transporters and enzymes. Of interest to drug designers is their high potency combined with their resistance to many proteases.

Of particular interest are venoms from the Conidae, with smaller polypeptide chains of 10-30 amino acids that are highly constrained by two to four disulfide bridges and structurally well-defined. Their high potency and exquisite selectivity for ion channels and receptors has led to two drug candidates [2,3] from our laboratories.

In this presentation I will outline the use of selenocysteine, the 21st coded amino acid to direct native folding and produce peptides with improved biophysical properties. By replacing complementary cysteine pairs with isosteric selenocysteine pairs or generating isosteric thioether or selenoether mimetics, we were able to chemically control the shape, stability and functionality of small peptides that target the neuronal nicotinic receptor and the oxytocin receptor. Together, these results underpin the development of more stable and potent nicotinic antagonists and OT agonists suitable for new drug therapies, and highlight the application of this technology more broadly to disulfide-bonded peptides and proteins.

References

1. R. Myers, L. Cruz, J. Rivier, B. M. Olivera, Chem. Rev. 1993, 93, 1923.
2. R. L. Lewis, D. Adams, I. Sharpe, M. Loughnan, T. Bond, L. Thomas, A. Jones, J. Matheson, R. Drinkwater, K. Nielsen, D. J. Craik, P. F. Alewood, J. Biol. Chem. 2000, 275(45), 35335.
3. I. Sharpe, J. Gehrmann, M. Loughnan, L. Thomas, D. Adams, A. Atkins, D. J. Craik, D. Adams, P. F. Alewood, R. J. Lewis, Nature Neuroscience 2001, 4(9), 902.

Contact local IBMM : Dr. Jean-Alain Fehrentz (DAPP)

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