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Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na V Channel Inhibitor.
- Source :
-
Biomedicines [Biomedicines] 2020 Oct 02; Vol. 8 (10). Date of Electronic Publication: 2020 Oct 02. - Publication Year :
- 2020
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Abstract
- Voltage-gated sodium (Na <subscript>V</subscript> ) channel subtypes, including Na <subscript>V</subscript> 1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na <subscript>V</subscript> 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 <subscript>V</subscript> 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 <subscript>V</subscript> channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique Na <subscript>V</subscript> 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 <subscript>V</subscript> 1.7 putative pore blockers (IC <subscript>50</subscript> 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 <subscript>V</subscript> channel pore blocker selectivity and subsequently important for chronic pain drug development.
Details
- Language :
- English
- ISSN :
- 2227-9059
- Volume :
- 8
- Issue :
- 10
- Database :
- MEDLINE
- Journal :
- Biomedicines
- Publication Type :
- Academic Journal
- Accession number :
- 33023152
- Full Text :
- https://doi.org/10.3390/biomedicines8100391