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Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na(V) Channel Inhibitor
Voltage-gated sodium (Na(V)) channel subtypes, including Na(V)1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na(V) channel inhibitors which represent potential drug leads. Of the 22 µ-conotoxins character...
Autores principales: | , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
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MDPI
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599555/ https://www.ncbi.nlm.nih.gov/pubmed/33023152 http://dx.doi.org/10.3390/biomedicines8100391 |
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author | McMahon, Kirsten L. Tran, Hue N.T. Deuis, Jennifer R. Lewis, Richard J. Vetter, Irina Schroeder, Christina I. |
author_facet | McMahon, Kirsten L. Tran, Hue N.T. Deuis, Jennifer R. Lewis, Richard J. Vetter, Irina Schroeder, Christina I. |
author_sort | McMahon, Kirsten L. |
collection | PubMed |
description | Voltage-gated sodium (Na(V)) channel subtypes, including Na(V)1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na(V) 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 Na(V)1.7. 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 Na(V) channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique Na(V) channel selectivity profile (1.4 > 1.3 > 1.1 ≈ 1.6 ≈ 1.7 > 1.2 >> 1.5 ≈ 1.8) when compared to other µ-conotoxins and represents one of the most potent human Na(V)1.7 putative pore blockers (IC(50) 152.2 ± 21.8 nM) to date. NMR analysis reveals the structure of SxIIIC includes the characteristic α-helix seen in other µ-conotoxins. Future investigations into structure-activity relationships of SxIIIC are expected to provide insights into residues important for Na(V) channel pore blocker selectivity and subsequently important for chronic pain drug development. |
format | Online Article Text |
id | pubmed-7599555 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | MDPI |
record_format | MEDLINE/PubMed |
spelling | pubmed-75995552020-11-01 Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na(V) Channel Inhibitor McMahon, Kirsten L. Tran, Hue N.T. Deuis, Jennifer R. Lewis, Richard J. Vetter, Irina Schroeder, Christina I. Biomedicines Article Voltage-gated sodium (Na(V)) channel subtypes, including Na(V)1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na(V) 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 Na(V)1.7. 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 Na(V) channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique Na(V) channel selectivity profile (1.4 > 1.3 > 1.1 ≈ 1.6 ≈ 1.7 > 1.2 >> 1.5 ≈ 1.8) when compared to other µ-conotoxins and represents one of the most potent human Na(V)1.7 putative pore blockers (IC(50) 152.2 ± 21.8 nM) to date. NMR analysis reveals the structure of SxIIIC includes the characteristic α-helix seen in other µ-conotoxins. Future investigations into structure-activity relationships of SxIIIC are expected to provide insights into residues important for Na(V) channel pore blocker selectivity and subsequently important for chronic pain drug development. MDPI 2020-10-02 /pmc/articles/PMC7599555/ /pubmed/33023152 http://dx.doi.org/10.3390/biomedicines8100391 Text en © 2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/). |
spellingShingle | Article McMahon, Kirsten L. Tran, Hue N.T. Deuis, Jennifer R. Lewis, Richard J. Vetter, Irina Schroeder, Christina I. Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na(V) Channel Inhibitor |
title | Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na(V) Channel Inhibitor |
title_full | Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na(V) Channel Inhibitor |
title_fullStr | Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na(V) Channel Inhibitor |
title_full_unstemmed | Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na(V) Channel Inhibitor |
title_short | Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na(V) Channel Inhibitor |
title_sort | discovery, pharmacological characterisation and nmr structure of the novel µ-conotoxin sxiiic, a potent and irreversible na(v) channel inhibitor |
topic | Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7599555/ https://www.ncbi.nlm.nih.gov/pubmed/33023152 http://dx.doi.org/10.3390/biomedicines8100391 |
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