Cone snail venom peptide Vc1.1 selectively blocks human α9 and α3β2 nicotinic receptors involved in pain
α-Conotoxin Vc1.1 from cone snail venom selectively antagonized human α9 (IC50=160 nM) and α3β2 (IC50=232 nM) nicotinic receptors, with molecular dynamics revealing key binding determinants relevant to neuropathic and inflammatory pain treatment.
Quick Facts
What This Study Found
Vc1.1: selective for hα9 (IC50=160 nM) and hα3β2 (IC50=232 nM). α9[N179A]: 20-fold ↓potency (lost H-bond with D11). β2[E86A]: 4-fold ↑potency (K104 interaction). α9[N213K]: 2-fold ↑potency. MD simulations: D5 side chain interactions altered.
Key Numbers
How They Did This
Two-electrode voltage clamp in Xenopus oocytes expressing human nAChR subtypes. Site-directed mutagenesis (α9, β2). Molecular dynamics simulations. IC50 determination.
Why This Research Matters
α9 nAChRs mediate neuroinflammation and pain. A selective venom peptide that blocks these receptors provides a template for developing non-opioid pain treatments.
The Bigger Picture
Cone snail venoms have already yielded one FDA-approved pain drug (ziconotide). Vc1.1's selective blockade of α9 nAChRs for neuroinflammatory pain could lead to another venom-derived analgesic.
What This Study Doesn't Tell Us
Oocyte expression may not fully replicate native receptor pharmacology. Human subtype selectivity may differ from rat. In vivo pain data only in rats. Manufacturing of disulfide-rich peptides is complex.
Questions This Raises
- ?Can Vc1.1 analogues be designed with improved α9 selectivity?
- ?Would intranasal or intrathecal delivery enable clinical use?
- ?How does α9 blockade compare to CGRP blockade for neuropathic pain?
Trust & Context
- Key Stat:
- 160 nM selective α9 blockade Cone snail venom peptide Vc1.1 selectively targets α9 nicotinic receptors involved in neuroinflammation at nanomolar potency—a template for non-opioid pain drugs
- Evidence Grade:
- Rigorous electrophysiology and molecular dynamics study. Strong structure-activity data for rational drug design.
- Study Age:
- Published in 2025.
- Original Title:
- Molecular determinants of the selectivity and potency of α-conotoxin Vc1.1 for human nicotinic acetylcholine receptors.
- Published In:
- The Journal of biological chemistry, 301(1), 108017 (2025)
- Authors:
- Tae, Han-Shen, Hung, Andrew(3), Clark, Richard J(4), Adams, David J
- Database ID:
- RPEP-13744
Evidence Hierarchy
Frequently Asked Questions
Can snail venom treat pain?
Cone snails produce potent peptide toxins that block pain receptors. Vc1.1, a 16-amino acid peptide from Conus victoriae, blocks specific nicotinic receptors (α9) involved in neuroinflammation and pain at very low concentrations. One cone snail peptide (ziconotide) is already an approved pain drug.
Why is α9 receptor selectivity important?
α9 nicotinic receptors are specifically involved in neuroinflammation and pain signaling. Blocking them could provide pain relief without the addiction risk of opioids or the broad side effects of drugs targeting more common receptor subtypes. Vc1.1's natural selectivity for α9 makes it an ideal starting point for drug design.
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Cite This Study
https://rethinkpeptides.com/research/RPEP-13744APA
Tae, Han-Shen; Hung, Andrew; Clark, Richard J; Adams, David J. (2025). Molecular determinants of the selectivity and potency of α-conotoxin Vc1.1 for human nicotinic acetylcholine receptors.. The Journal of biological chemistry, 301(1), 108017. https://doi.org/10.1016/j.jbc.2024.108017
MLA
Tae, Han-Shen, et al. "Molecular determinants of the selectivity and potency of α-conotoxin Vc1.1 for human nicotinic acetylcholine receptors.." The Journal of biological chemistry, 2025. https://doi.org/10.1016/j.jbc.2024.108017
RethinkPeptides
RethinkPeptides Research Database. "Molecular determinants of the selectivity and potency of α-c..." RPEP-13744. Retrieved from https://rethinkpeptides.com/research/tae-2025-molecular-determinants-of-the
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Study data sourced from PubMed, a service of the U.S. National Library of Medicine, National Institutes of Health.
This study breakdown was produced by the RethinkPeptides research team. We analyze and report published research findings without making health recommendations. All interpretations are based solely on the published abstract and study data.