6x8r

Publication Abstract from PubMed

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

Discovery, Pharmacological Characterisation and NMR Structure of the Novel micro-Conotoxin SxIIIC, a Potent and Irreversible NaV Channel Inhibitor.,McMahon KL, Tran HNT, Deuis JR, Lewis RJ, Vetter I, Schroeder CI Biomedicines. 2020 Oct 2;8(10). pii: biomedicines8100391. doi:, 10.3390/biomedicines8100391. PMID:33023152^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.