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

Author:

McMahon, Kirsten L [ORCID]

Tran, Hue N T [ORCID]

Deuis, Jennifer R

Lewis, Richard J

Vetter, Irina [ORCID]

Schroeder,Christina [ORCID]
Author Address

Institute for Molecular Bioscience, The University of Queensland, Brisbane, QLD 4072, Australia., The School of Pharmacy, The University of Queensland, Woolloongabba, QLD 4102, Australia., National Cancer Institute, National Institutes of Health, Frederick, MD 21702, USA.,

Abstract:

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 181;-conotoxins are small, potent NaV channel inhibitors which represent potential drug leads. Of the 22 181;-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 181;-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 ˜ 1.6 ˜ 1.7 > 1.2 > 1.5 ˜ 1.8) when compared to other 181;-conotoxins and represents one of the most potent human NaV1.7 putative pore blockers (IC50 152.2 177; 21.8 nM) to date. NMR analysis reveals the structure of SxIIIC includes the characteristic a-helix seen in other 181;-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.

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