Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7
dc.contributor.author | Agwa, A. | |
dc.contributor.author | Lawrence, N. | |
dc.contributor.author | Deplazes, Evelyne | |
dc.contributor.author | Cheneval, O. | |
dc.contributor.author | Chen, R. | |
dc.contributor.author | Craik, D. | |
dc.contributor.author | Schroeder, C. | |
dc.contributor.author | Henriques, S. | |
dc.date.accessioned | 2017-03-15T22:24:10Z | |
dc.date.available | 2017-03-15T22:24:10Z | |
dc.date.created | 2017-03-08T06:39:37Z | |
dc.date.issued | 2017 | |
dc.identifier.citation | Agwa, 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.uri | http://hdl.handle.net/20.500.11937/50471 | |
dc.identifier.doi | 10.1016/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.publisher | Elsevier | |
dc.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 | |
dc.type | Journal Article | |
dcterms.source.volume | 1859 | |
dcterms.source.number | 5 | |
dcterms.source.startPage | 835 | |
dcterms.source.endPage | 844 | |
dcterms.source.issn | 0005-2736 | |
dcterms.source.title | Biochimica et Biophysica Acta. Biomembranes | |
curtin.department | School of Biomedical Sciences | |
curtin.accessStatus | Open access |