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dc.contributor.authorAgwa, A.
dc.contributor.authorLawrence, N.
dc.contributor.authorDeplazes, Evelyne
dc.contributor.authorCheneval, O.
dc.contributor.authorChen, R.
dc.contributor.authorCraik, D.
dc.contributor.authorSchroeder, C.
dc.contributor.authorHenriques, S.
dc.identifier.citationAgwa, A. and Lawrence, N. and Deplazes, E. and Cheneval, O. and Chen, R. and Craik, D. and Schroeder, C. et al. 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): pp. 835-844.

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.

dc.titleSpider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7
dc.typeJournal Article
dcterms.source.titleBiochimica et Biophysica Acta. Biomembranes
curtin.departmentSchool of Biomedical Sciences
curtin.accessStatusOpen access

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