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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.date.accessioned2017-03-15T22:24:10Z
dc.date.available2017-03-15T22:24:10Z
dc.date.created2017-03-08T06:39:37Z
dc.date.issued2017
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.
dc.identifier.urihttp://hdl.handle.net/20.500.11937/50471
dc.identifier.doi10.1016/j.bbamem.2017.01.020
dc.description.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.

dc.publisherElsevier
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.volume1859
dcterms.source.number5
dcterms.source.startPage835
dcterms.source.endPage844
dcterms.source.issn0005-2736
dcterms.source.titleBiochimica et Biophysica Acta. Biomembranes
curtin.departmentSchool of Biomedical Sciences
curtin.accessStatusOpen access


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