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Effects of cyclization on stability, structure, and activity of α-conotoxin RgIA at the α9α10 nicotinic acetylcholine receptor and GABAB receptor

Journal Article


Abstract


  • α-Conotoxin RgIA is of interest as a lead in the development of drugs for neuropathic pain. It modulates the α9α10 nicotinic acetylcholine receptor (nAChR) and the GABAB receptor, both of which are implicated in antinociception. However, because of its peptidic nature, RgIA is potentially susceptible to generic problems encountered by peptide-based drugs of poor oral bioavailability, short biological half-life, and low stability. Here, we improved the biopharmaceutical properties of RgIA by backbone cyclization using 3–7 residue peptidic linkers. Cyclization with a six-residue linker does not perturb the overall structure of RgIA, improves selectivity for the GABAB receptor over the α9α10 nAChR, and improves stability in human serum. The results provide insights to further improve the therapeutic properties of RgIA and other conotoxins being considered as drug leads and confirm that cyclization is a readily applicable strategy to improve the stability of peptides with proximate N- and C-termini.

UOW Authors


  •   Halai, Reena (external author)
  •   Callaghan, Brid P. (external author)
  •   Daly, Norelle L. (external author)
  •   Clark, Richard J. (external author)
  •   Adams, David
  •   Craik, David J. (external author)

Publication Date


  • 2011

Citation


  • Halai, R., Callaghan, B., Daly, N. L., Clark, R. J., Adams, D. J. & Craik, D. J. (2011). Effects of cyclization on stability, structure, and activity of α-conotoxin RgIA at the α9α10 nicotinic acetylcholine receptor and GABAB receptor. Journal of Medicinal Chemistry, 54 (19), 6984-6992.

Scopus Eid


  • 2-s2.0-80053923631

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/618

Number Of Pages


  • 8

Start Page


  • 6984

End Page


  • 6992

Volume


  • 54

Issue


  • 19

Abstract


  • α-Conotoxin RgIA is of interest as a lead in the development of drugs for neuropathic pain. It modulates the α9α10 nicotinic acetylcholine receptor (nAChR) and the GABAB receptor, both of which are implicated in antinociception. However, because of its peptidic nature, RgIA is potentially susceptible to generic problems encountered by peptide-based drugs of poor oral bioavailability, short biological half-life, and low stability. Here, we improved the biopharmaceutical properties of RgIA by backbone cyclization using 3–7 residue peptidic linkers. Cyclization with a six-residue linker does not perturb the overall structure of RgIA, improves selectivity for the GABAB receptor over the α9α10 nAChR, and improves stability in human serum. The results provide insights to further improve the therapeutic properties of RgIA and other conotoxins being considered as drug leads and confirm that cyclization is a readily applicable strategy to improve the stability of peptides with proximate N- and C-termini.

UOW Authors


  •   Halai, Reena (external author)
  •   Callaghan, Brid P. (external author)
  •   Daly, Norelle L. (external author)
  •   Clark, Richard J. (external author)
  •   Adams, David
  •   Craik, David J. (external author)

Publication Date


  • 2011

Citation


  • Halai, R., Callaghan, B., Daly, N. L., Clark, R. J., Adams, D. J. & Craik, D. J. (2011). Effects of cyclization on stability, structure, and activity of α-conotoxin RgIA at the α9α10 nicotinic acetylcholine receptor and GABAB receptor. Journal of Medicinal Chemistry, 54 (19), 6984-6992.

Scopus Eid


  • 2-s2.0-80053923631

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/618

Number Of Pages


  • 8

Start Page


  • 6984

End Page


  • 6992

Volume


  • 54

Issue


  • 19