Spider peptide toxin HwTx-IV engineered to bind to lipid membranes has an increased inhibitory potency at human voltage-gated sodium channel hNaV1.7.
- Publisher:
- ELSEVIER SCIENCE BV
- Publication Type:
- Journal Article
- Citation:
- Biochim Biophys Acta Biomembr, 2017, 1859, (5), pp. 835-844
- Issue Date:
- 2017-05
Closed Access
Filename | Description | Size | |||
---|---|---|---|---|---|
1-s2.0-S0005273617300287-mainext.pdf | 1.67 MB | Adobe PDF |
Copyright Clearance Process
- Recently Added
- In Progress
- Closed Access
This item is closed access and not available.
Full metadata record
Field | Value | Language |
---|---|---|
dc.contributor.author | Agwa, AJ | |
dc.contributor.author | Lawrence, N | |
dc.contributor.author |
Deplazes, E https://orcid.org/0000-0003-2052-5536 |
|
dc.contributor.author | Cheneval, O | |
dc.contributor.author | Chen, RM | |
dc.contributor.author | Craik, DJ | |
dc.contributor.author | Schroeder, CI | |
dc.contributor.author | Henriques, ST | |
dc.date.accessioned | 2022-03-24T05:28:33Z | |
dc.date.available | 2017-01-19 | |
dc.date.available | 2022-03-24T05:28:33Z | |
dc.date.issued | 2017-05 | |
dc.identifier.citation | Biochim Biophys Acta Biomembr, 2017, 1859, (5), pp. 835-844 | |
dc.identifier.issn | 0005-2736 | |
dc.identifier.issn | 1879-2642 | |
dc.identifier.uri | http://hdl.handle.net/10453/155515 | |
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.format | Print-Electronic | |
dc.language | eng | |
dc.publisher | ELSEVIER SCIENCE BV | |
dc.relation.ispartof | Biochim Biophys Acta Biomembr | |
dc.relation.isbasedon | 10.1016/j.bbamem.2017.01.020 | |
dc.rights | info:eu-repo/semantics/closedAccess | |
dc.subject | 0601 Biochemistry and Cell Biology, 0699 Other Biological Sciences, 0904 Chemical Engineering | |
dc.subject.classification | Biochemistry & Molecular Biology | |
dc.subject.classification | Biophysics | |
dc.subject.mesh | Biophysical Phenomena | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Lipid Bilayers | |
dc.subject.mesh | Magnetic Resonance Spectroscopy | |
dc.subject.mesh | NAV1.7 Voltage-Gated Sodium Channel | |
dc.subject.mesh | Sodium Channel Blockers | |
dc.subject.mesh | Spectrometry, Fluorescence | |
dc.subject.mesh | Spider Venoms | |
dc.subject.mesh | Surface Plasmon Resonance | |
dc.subject.mesh | Humans | |
dc.subject.mesh | Lipid Bilayers | |
dc.subject.mesh | Sodium Channel Blockers | |
dc.subject.mesh | Spider Venoms | |
dc.subject.mesh | Spectrometry, Fluorescence | |
dc.subject.mesh | Magnetic Resonance Spectroscopy | |
dc.subject.mesh | Surface Plasmon Resonance | |
dc.subject.mesh | Biophysical Phenomena | |
dc.subject.mesh | NAV1.7 Voltage-Gated Sodium Channel | |
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 | |
utslib.citation.volume | 1859 | |
utslib.location.activity | Netherlands | |
utslib.for | 0601 Biochemistry and Cell Biology | |
utslib.for | 0699 Other Biological Sciences | |
utslib.for | 0904 Chemical Engineering | |
pubs.organisational-group | /University of Technology Sydney | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science | |
pubs.organisational-group | /University of Technology Sydney/Faculty of Science/School of Life Sciences | |
utslib.copyright.status | closed_access | * |
dc.date.updated | 2022-03-24T05:28:32Z | |
pubs.issue | 5 | |
pubs.publication-status | Published | |
pubs.volume | 1859 | |
utslib.citation.issue | 5 |
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.
Please use this identifier to cite or link to this item:
Download statistics for the last 12 months
Not enough data to produce graph