Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7

Akello J Agwa, Nicole Lawrence, Evelyne Deplazes, Olivier Cheneval, Rachel M Chen, David J Craik, Christina I Schroeder, Sónia T Henriques

Research output: Contribution to journalArticlepeer-review

28 Citations (Scopus)

Abstract

The human voltage-gated sodium channel sub-type 1.7 (hNaV1.7) is emerging as an attractive target for the development of potent and sub-type selective novel analgesics with increased potency and fewer side effects than existing therapeutics. HwTx-IV, a spider derived peptide toxin, inhibits hNaV1.7 with high potency and is therefore of great interest as an analgesic lead. In the current study we examined whether engineering a HwTx-IV analogue with increased ability to bind to lipid membranes would improve its inhibitory potency at hNaV1.7. This hypothesis was explored by comparing HwTx-IV and two analogues [E1PyrE]HwTx-IV (mHwTx-IV) and [E1G,E4G,F6W,Y30W]HwTx-IV (gHwTx-IV) on their membrane-binding affinity and hNaV1.7 inhibitory potency using a range of biophysical techniques including computational analysis, NMR spectroscopy, surface plasmon resonance, and fluorescence spectroscopy. HwTx-IV and mHwTx-IV exhibited weak affinity for lipid membranes, whereas gHwTx-IV showed improved affinity for the model membranes studied. In addition, activity assays using SH-SY5Y neuroblastoma cells expressing hNaV1.7 showed that gHwTx-IV has increased activity at hNaV1.7 compared to HwTx-IV. Based on these results we hypothesize that an increase in the affinity of HwTx-IV for lipid membranes is accompanied by improved inhibitory potency at hNaV1.7 and that increasing the affinity of gating modifier toxins to lipid bilayers is a strategy that may be useful for improving their potency at hNaV1.7.

Original languageEnglish
Pages (from-to)835-844
Number of pages10
JournalBiochimica Et Biophysica Acta-Biomembranes
Volume1859
Issue number5
DOIs
Publication statusPublished - May 2017

Keywords

  • Biophysical Phenomena
  • Humans
  • Lipid Bilayers/metabolism
  • Magnetic Resonance Spectroscopy
  • NAV1.7 Voltage-Gated Sodium Channel/drug effects
  • Sodium Channel Blockers/pharmacology
  • Spectrometry, Fluorescence
  • Spider Venoms/metabolism
  • Surface Plasmon Resonance

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