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

Agwa, Akello J., Lawrence, Nicole , Deplazes, Evelyne, Cheneval, Olivier, Chen, Rachel M., Craik, David J., Schroeder, Christina I. and Henriques, Sónia T. (2017) Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7. Biochimica et Biophysica Acta. Biomembranes, 1859 5: 835-844. doi:10.1016/j.bbamem.2017.01.020


Author Agwa, Akello J.
Lawrence, Nicole
Deplazes, Evelyne
Cheneval, Olivier
Chen, Rachel M.
Craik, David J.
Schroeder, Christina I.
Henriques, Sónia T.
Title Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7
Formatted title
Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7
Journal name Biochimica et Biophysica Acta. Biomembranes   Check publisher's open access policy
ISSN 0005-2736
1879-2642
Publication date 2017-05-01
Sub-type Article (original research)
DOI 10.1016/j.bbamem.2017.01.020
Open Access Status Not yet assessed
Volume 1859
Issue 5
Start page 835
End page 844
Total pages 10
Place of publication Amsterdam, Netherlands
Publisher Elsevier BV
Language eng
Formatted 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.
Keyword Drug design
Gating modifier toxin
Huwentoxin
Pain therapeutic
Peptide-membrane interactions
Venom peptide
Q-Index Code C1
Q-Index Status Provisional Code
Institutional Status UQ

Document type: Journal Article
Sub-type: Article (original research)
Collections: HERDC Pre-Audit
School of Chemistry and Molecular Biosciences
Institute for Molecular Bioscience - Publications
 
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