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Engineering stable peptide toxins by means of backbone cyclization: stabilization of the α-conotoxin MII

Journal Article


Abstract


  • Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the α-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.

UOW Authors


  •   Clark, Richard J. (external author)
  •   Fischer, Harald (external author)
  •   Dempster, Louise (external author)
  •   Daly, Norelle L. (external author)
  •   Rosengren, K. . Johan (external author)
  •   Nevin, Simon T. (external author)
  •   Meunier, Frederic A. (external author)
  •   Adams, David
  •   Craik, David J. (external author)

Publication Date


  • 2005

Citation


  • Clark, R. J., Fischer, H., Dempster, L., Daly, N. L., Rosengren, K., Nevin, S. T., Meunier, F. A., Adams, D. J. & Craik, D. J. (2005). Engineering stable peptide toxins by means of backbone cyclization: stabilization of the α-conotoxin MII. Proceedings of the National Academy of Sciences of USA, 102 (39), 13767-13772.

Scopus Eid


  • 2-s2.0-25444448796

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/665

Number Of Pages


  • 5

Start Page


  • 13767

End Page


  • 13772

Volume


  • 102

Issue


  • 39

Abstract


  • Conotoxins (CTXs), with their exquisite specificity and potency, have recently created much excitement as drug leads. However, like most peptides, their beneficial activities may potentially be undermined by susceptibility to proteolysis in vivo. By cyclizing the α-CTX MII by using a range of linkers, we have engineered peptides that preserve their full activity but have greatly improved resistance to proteolytic degradation. The cyclic MII analogue containing a seven-residue linker joining the N and C termini was as active and selective as the native peptide for native and recombinant neuronal nicotinic acetylcholine receptor subtypes present in bovine chromaffin cells and expressed in Xenopus oocytes, respectively. Furthermore, its resistance to proteolysis against a specific protease and in human plasma was significantly improved. More generally, to our knowledge, this report is the first on the cyclization of disulfide-rich toxins. Cyclization strategies represent an approach for stabilizing bioactive peptides while keeping their full potencies and should boost applications of peptide-based drugs in human medicine.

UOW Authors


  •   Clark, Richard J. (external author)
  •   Fischer, Harald (external author)
  •   Dempster, Louise (external author)
  •   Daly, Norelle L. (external author)
  •   Rosengren, K. . Johan (external author)
  •   Nevin, Simon T. (external author)
  •   Meunier, Frederic A. (external author)
  •   Adams, David
  •   Craik, David J. (external author)

Publication Date


  • 2005

Citation


  • Clark, R. J., Fischer, H., Dempster, L., Daly, N. L., Rosengren, K., Nevin, S. T., Meunier, F. A., Adams, D. J. & Craik, D. J. (2005). Engineering stable peptide toxins by means of backbone cyclization: stabilization of the α-conotoxin MII. Proceedings of the National Academy of Sciences of USA, 102 (39), 13767-13772.

Scopus Eid


  • 2-s2.0-25444448796

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/665

Number Of Pages


  • 5

Start Page


  • 13767

End Page


  • 13772

Volume


  • 102

Issue


  • 39