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Combining Two Venom Peptides Into One Creates a Better Pain Channel Blocker

RPEP-051712020Tran, Hue N T; Tran, Poanna; Deuis, Jennifer R; Agwa, Akello J; Zhang, Alan H; Vetter, Irina; Schroeder, Christina I
In VitroPreliminary evidence
The takeaway

Enzymatically ligating a pore-blocking cone snail peptide with a gating-modifier spider peptide creates a bivalent NaV1.7 inhibitor with enhanced potency for pain treatment.

Bivalent

First double-knotted peptide combining two venom toxins to simultaneously block two NaV1.7 binding sites

What the researchers found

Enzymatic ligation of two venom peptides targeting different NaV1.7 binding sites creates a bivalent inhibitor with enhanced sodium channel blockade.

Why it matters

NaV1.7 is a genetically validated pain target, but single-site inhibitors haven't achieved sufficient clinical efficacy. Bivalent inhibitors hitting two sites simultaneously could finally unlock this target.

The numbers in context

9-AA optimal linker; improved affinity/potency vs PaurTx3 or KIIIA alone; sortase A ligation

How the study worked

Evolved sortase A-mediated enzymatic ligation, electrophysiology for NaV1.7 inhibition measurement, structural characterization of double-knotted peptides.

Who was studied

In vitro NaV1.7 electrophysiology

What this study cannot tell us

In vitro electrophysiology data only. In vivo pain relief not demonstrated. Manufacturing complexity of double-knotted peptides may limit clinical development.

How to read the evidence

In vitro proof-of-concept with electrophysiology data. Innovative approach at early discovery stage.

When this study was published

Published in 2020. NaV1.7-targeted pain therapeutics remain an active area of drug development.

The bigger picture

This bivalent approach could be applied to other ion channel targets, creating more potent and selective peptide therapeutics by simultaneously engaging multiple binding sites.

Questions still open

  • Does bivalent NaV1.7 inhibition produce better pain relief in animal models?
  • Can the double-knotted peptide be produced at scale?
  • Does simultaneous dual-site binding improve NaV1.7 selectivity over other sodium channels?

Common questions

Why is NaV1.7 important for pain?
People born without functional NaV1.7 channels feel no pain, proving this sodium channel is essential for pain signaling. However, drugs targeting just one site on NaV1.7 haven't been effective enough clinically, motivating the dual-site approach.
How were two venom peptides combined?
Using an enzyme called evolved sortase A, researchers chemically linked a spider toxin (which targets NaV1.7's voltage sensor) to a cone snail toxin (which blocks the channel pore). The resulting double-knotted peptide can engage both sites simultaneously for stronger inhibition.

Read the original research

Enzymatic Ligation of a Pore Blocker Toxin and a Gating Modifier Toxin: Creating Double-Knotted Peptides with Improved Sodium Channel NaV1.7 Inhibition.

Bioconjugate chemistry, 31(1), 64-73

View on PubMed ↗Publisher’s paper ↗

Citation

Tran, Hue N T; Tran, Poanna; Deuis, Jennifer R; Agwa, Akello J; Zhang, Alan H; Vetter, Irina; Schroeder, Christina I. (2020). Enzymatic Ligation of a Pore Blocker Toxin and a Gating Modifier Toxin: Creating Double-Knotted Peptides with Improved Sodium Channel NaV1.7 Inhibition.. Bioconjugate chemistry, 31(1), 64-73. https://doi.org/10.1021/acs.bioconjchem.9b00744