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

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.

► χ-Conopeptide are highly selectively inhibitors of norepinephrine transporter.
► χ-MrIA reversed signs of mechanical allodynia in rats but was unstable.
► Xen2174 had improved stability and an extended duration of analgaesia.
► Xen2174 relieved pain in cancer patients over multiple days.
► Xen2174 is now being prepared for a Phase IIb study in bunionectomy pain.