title: Discovery and development of the χ-conopeptide class of analgesic peptides.
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.
authors.affiliation: Institute for Molecular Bioscience, The University of Queensland, Australia. r.lewis@imb.uq.edu.au
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Lewis
mesh_terms: D000409:Alanine / Q000378:metabolism; D000595:Amino Acid Sequence; D000700:Analgesics / Q000494:pharmacology*; D000818:Animals; D059350:Chronic Pain / Q000188:drug therapy; D020916:Conotoxins / Q000737:chemistry* / Q000494:pharmacology*; D006801:Humans; D008969:Molecular Sequence Data; D009369:Neoplasms / Q000188:drug therapy; D050484:Norepinephrine Plasma Membrane Transport Proteins / Q000037:antagonists & inhibitors / Q000302:isolation & purification; D010455:Peptides / Q000494:pharmacology; D011487:Protein Conformation; D051381:Rats
chemical_list: D000700:Analgesics; D020916:Conotoxins; D050484:Norepinephrine Plasma Membrane Transport Proteins; D010455:Peptides; C500187:Xen2174; C507563:chi-conopeptide MrIA, Conus; D000409:Alanine