Cargando…

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...

Descripción completa

Detalles Bibliográficos
Autores principales: McMahon, Kirsten L., Tran, Hue N.T., Deuis, Jennifer R., Lewis, Richard J., Vetter, Irina, Schroeder, Christina I.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2020
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
_version_ 1783602903864311808
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
work_keys_str_mv AT mcmahonkirstenl discoverypharmacologicalcharacterisationandnmrstructureofthenovelμconotoxinsxiiicapotentandirreversiblenavchannelinhibitor
AT tranhuent discoverypharmacologicalcharacterisationandnmrstructureofthenovelμconotoxinsxiiicapotentandirreversiblenavchannelinhibitor
AT deuisjenniferr discoverypharmacologicalcharacterisationandnmrstructureofthenovelμconotoxinsxiiicapotentandirreversiblenavchannelinhibitor
AT lewisrichardj discoverypharmacologicalcharacterisationandnmrstructureofthenovelμconotoxinsxiiicapotentandirreversiblenavchannelinhibitor
AT vetteririna discoverypharmacologicalcharacterisationandnmrstructureofthenovelμconotoxinsxiiicapotentandirreversiblenavchannelinhibitor
AT schroederchristinai discoverypharmacologicalcharacterisationandnmrstructureofthenovelμconotoxinsxiiicapotentandirreversiblenavchannelinhibitor