Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible NaV Channel Inhibitor
| العنوان: | Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible NaV Channel Inhibitor |
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| المؤلفون: | Richard J. Lewis, Jennifer R. Deuis, Christina I. Schroeder, Irina Vetter, Hue N. T. Tran, Kirsten L. McMahon |
| المصدر: | Biomedicines, Vol 8, Iss 391, p 391 (2020) Biomedicines Volume 8 Issue 10 |
| بيانات النشر: | MDPI AG, 2020. |
| سنة النشر: | 2020 |
| مصطلحات موضوعية: | 0301 basic medicine, Medicine (miscellaneous), Peptide, Chemical synthesis, General Biochemistry, Genetics and Molecular Biology, Article, NaV channels, 03 medical and health sciences, 0302 clinical medicine, pore blocker, Conotoxin, lcsh:QH301-705.5, Conus striolatus, chemistry.chemical_classification, biology, biology.organism_classification, µ-conotoxin, Nav channel, whole-cell patch-clamp electrophysiology, NMR, Electrophysiology, 030104 developmental biology, Drug development, chemistry, lcsh:Biology (General), Biophysics, Selectivity, chronic pain, 030217 neurology & neurosurgery |
| الوصف: | Voltage-gated sodium (NaV) channel subtypes, including NaV1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ conotoxins are small, potent NaV channel inhibitors which represent potential drug leads. Of the 22 µ conotoxins characterised so far, only a small number, including KIIIA and CnIIIC, have shown inhibition against human NaV1.7. We have recently identified a novel µ conotoxin, SxIIIC, from Conus striolatus. Here we present the isolation of native peptide, chemical synthesis, characterisation of human NaV channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique NaV channel selectivity profile (1.4 > 1.3 > 1.1 &asymp 1.6 &asymp 1.7 > 1.2 > > 1.5 &asymp 1.8) when compared to other µ conotoxins and represents one of the most potent human NaV1.7 putative pore blockers (IC50 152.2 ± 21.8 nM) to date. NMR analysis reveals the structure of SxIIIC includes the characteristic &alpha helix seen in other µ conotoxins. Future investigations into structure-activity relationships of SxIIIC are expected to provide insights into residues important for NaV channel pore blocker selectivity and subsequently important for chronic pain drug development. |
| وصف الملف: | application/pdf |
| اللغة: | English |
| تدمد: | 2227-9059 |
| URL الوصول: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::3f0184e2fd8575c973687acb1ff4e20b https://www.mdpi.com/2227-9059/8/10/391 |
| Rights: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....3f0184e2fd8575c973687acb1ff4e20b |
| قاعدة البيانات: | OpenAIRE |
| تدمد: | 22279059 |
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