Skip to main content
placeholder image

Structure-activity studies of cysteine-rich α-Conotoxins that inhibit high voltage-activated calcium channels via GABAB receptor activation reveal a minimal functional motif

Journal Article


Download full-text (Open Access)

Abstract


  • α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABAB receptor (GABABR) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABABR activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs.

UOW Authors


  •   Carstens, Bodil B. (external author)
  •   Berecki, Géza (external author)
  •   Daniel, James T. (external author)
  •   Lee, Han Siean (external author)
  •   Jackson, Kathryn A. V. (external author)
  •   Tae, Han Shen
  •   Sadeghi, Mahsa (external author)
  •   Castro, Joel (external author)
  •   O'Donnell, Tracy (external author)
  •   Deiteren, Annemie (external author)
  •   Brierley, Stuart (external author)
  •   Craik, David J. (external author)
  •   Adams, David
  •   Clark, Richard J. (external author)

Publication Date


  • 2016

Citation


  • Carstens, B. B., Berecki, G., Daniel, J. T., Lee, H., Jackson, K. A. V., Tae, H., Sadeghi, M., Castro, J., O'Donnell, T., Deiteren, A., Brierley, S. M., Craik, D. J., Adams, D. J. & Clark, R. J. (2016). Structure-activity studies of cysteine-rich α-Conotoxins that inhibit high voltage-activated calcium channels via GABAB receptor activation reveal a minimal functional motif. Angewandte Chemie International Edition, 55 (15), 4692-4696.

Scopus Eid


  • 2-s2.0-84960172454

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1849&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/826

Number Of Pages


  • 4

Start Page


  • 4692

End Page


  • 4696

Volume


  • 55

Issue


  • 15

Abstract


  • α-Conotoxins are disulfide-rich peptides that target nicotinic acetylcholine receptors. Recently we identified several α-conotoxins that also modulate voltage-gated calcium channels by acting as G protein-coupled GABAB receptor (GABABR) agonists. These α-conotoxins are promising drug leads for the treatment of chronic pain. To elucidate the diversity of α-conotoxins that act through this mechanism, we synthesized and characterized a set of peptides with homology to α-conotoxins known to inhibit high voltage-activated calcium channels via GABABR activation. Remarkably, all disulfide isomers of the active α-conotoxins Pu1.2 and Pn1.2, and the previously studied Vc1.1 showed similar levels of biological activity. Structure determination by NMR spectroscopy helped us identify a simplified biologically active eight residue peptide motif containing a single disulfide bond that is an excellent lead molecule for developing a new generation of analgesic peptide drugs.

UOW Authors


  •   Carstens, Bodil B. (external author)
  •   Berecki, Géza (external author)
  •   Daniel, James T. (external author)
  •   Lee, Han Siean (external author)
  •   Jackson, Kathryn A. V. (external author)
  •   Tae, Han Shen
  •   Sadeghi, Mahsa (external author)
  •   Castro, Joel (external author)
  •   O'Donnell, Tracy (external author)
  •   Deiteren, Annemie (external author)
  •   Brierley, Stuart (external author)
  •   Craik, David J. (external author)
  •   Adams, David
  •   Clark, Richard J. (external author)

Publication Date


  • 2016

Citation


  • Carstens, B. B., Berecki, G., Daniel, J. T., Lee, H., Jackson, K. A. V., Tae, H., Sadeghi, M., Castro, J., O'Donnell, T., Deiteren, A., Brierley, S. M., Craik, D. J., Adams, D. J. & Clark, R. J. (2016). Structure-activity studies of cysteine-rich α-Conotoxins that inhibit high voltage-activated calcium channels via GABAB receptor activation reveal a minimal functional motif. Angewandte Chemie International Edition, 55 (15), 4692-4696.

Scopus Eid


  • 2-s2.0-84960172454

Ro Full-text Url


  • http://ro.uow.edu.au/cgi/viewcontent.cgi?article=1849&context=ihmri

Ro Metadata Url


  • http://ro.uow.edu.au/ihmri/826

Number Of Pages


  • 4

Start Page


  • 4692

End Page


  • 4696

Volume


  • 55

Issue


  • 15