posted on 2021-06-18, 14:43authored byJoanna Gajewiak, Sean B. Christensen, Cheryl Dowell, Fuaad Hararah, Fernando Fisher, Peter N. Huynh, Baldomero M. Olivera, J. Michael McIntosh
Venom-derived compounds are of broad
interest in neuropharmacology
and drug development. α-Conotoxins are small disulfide-containing
peptides from Conus snails that target nicotinic
acetylcholine receptors (nAChRs) and are in clinical development for
non-opioid-based treatment of intractable pain. Although refined by
evolution for interaction with target prey receptors, enhancements
of pharmacological properties are needed for use in mammalian systems.
Therefore, we synthesized analogues of α-conotoxin RgIA using
a combination of selective penicillamine substitutions together with
natural and non-natural amino acid replacements. This approach resulted
in a peptide with 9000-fold increased potency on the human α9α10
nAChR and improved resistance to disulfide shuffling compared to the
native peptide. The lead analogue, RgIA-5474, potently blocked α9α10
nAChRs, but not opioid- or other pain-related targets. In addition,
RgIA-5474 effectively reversed chemotherapy-induced neuropathic pain.