Discovery and development of the chi-conopeptide class of analgesic peptides

Lewis, Richard J. (2012) Discovery and development of the chi-conopeptide class of analgesic peptides. Toxicon, 59 4: 524-528. doi:10.1016/j.toxicon.2011.07.012

Author Lewis, Richard J.
Title Discovery and development of the chi-conopeptide class of analgesic peptides
Formatted title
Discovery and development of the χ-conopeptide class of analgesic peptides
Journal name Toxicon   Check publisher's open access policy
ISSN 0041-0101
Publication date 2012-03-15
Year available 2011
Sub-type Article (original research)
DOI 10.1016/j.toxicon.2011.07.012
Volume 59
Issue 4
Start page 524
End page 528
Total pages 5
Editor Reto Stöcklin
Alan Harvey
Place of publication Kidlington, Oxford, United Kingdom
Publisher Pergamon
Language eng
Formatted abstract
Cone snail venoms continue to provide a rich source of bioactive peptides useful as research tools and leads to new therapeutics. We isolated two closely related conopeptides, MrIA and MrIB, which defined the χ-conopeptide class of bioactive peptides based on their unique ability to highly selectively and non-competitively inhibit the norepinephrine transporter (NET). An alanine scan of χ-MrIA revealed this class of peptides had a unusual cysteine-stabilised scaffold that presented a γ-turn in an optimised conformation for high affinity interactions with NET. χ-MrIA reversed the behavioural signs of mechanical allodynia in a chronic constriction injury rat model but its chemically unstable N-terminal asparagine precluded long-term use in implanted pumps. An extensive analoguing program identified Xen2174 to have improved stability and extended duration of analgaesia, without compromising efficacy versus side effects window observed forχ-MrIA. An open label, single IT bolus, dose-escalating study in cancer patients suffering severe chronic pain found Xen2174 relieved pain quickly over an extended period across a wide range of well-tolerated doses. Currently, Xen2174 is entering a Phase IIb double-blind study to determine safety and efficacy in bunionectomy pain.
Keyword Venom peptide
Cone snail
Norepinephrine transporter
Q-Index Code C1
Q-Index Status Confirmed Code
Institutional Status UQ
Additional Notes Available online 3 August 2011. Special issue: From venoms to drugs.

Document type: Journal Article
Sub-type: Article (original research)
Collections: Official 2012 Collection
Institute for Molecular Bioscience - Publications
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