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Papers of the Week

Papers: 3 Oct 2020 - 9 Oct 2020

Human Studies, Pharmacology/Drug Development

2020 Oct 02




Discovery, Pharmacological Characterisation and NMR Structure of the Novel µ-Conotoxin SxIIIC, a Potent and Irreversible Na Channel Inhibitor.


McMahon KL, Tran HNT, Deuis JR, Lewis RJ, Vetter I, Schroeder CI
Biomedicines. 2020 Oct 02; 8(10).
PMID: 33023152.


Voltage-gated sodium (Na) channel subtypes, including Na1.7, are promising targets for the treatment of neurological diseases, such as chronic pain. Cone snail-derived µ-conotoxins are small, potent Na 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 Na1.7. We have recently identified a novel µ-conotoxin, SxIIIC, from . Here we present the isolation of native peptide, chemical synthesis, characterisation of human Na channel activity by whole-cell patch-clamp electrophysiology and analysis of the NMR solution structure. SxIIIC displays a unique Na 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 Na1.7 putative pore blockers (IC 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 channel pore blocker selectivity and subsequently important for chronic pain drug development.