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. 2023 Sep:165:115173.
doi: 10.1016/j.biopha.2023.115173. Epub 2023 Jul 13.

Structure-function relationship of new peptides activating human Nav1.1

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Free article

Structure-function relationship of new peptides activating human Nav1.1

Ludivine Lopez et al. Biomed Pharmacother. 2023 Sep.
Free article

Abstract

Nav1.1 is an important pharmacological target as this voltage-gated sodium channel is involved in neurological and cardiac syndromes. Channel activators are actively sought to try to compensate for haploinsufficiency in several of these pathologies. Herein we used a natural source of new peptide compounds active on ion channels and screened for drugs capable to inhibit channel inactivation as a way to compensate for decreased channel function. We discovered that JzTx-34 is highly active on Nav1.1 and subsequently performed a full structure-activity relationship investigation to identify its pharmacophore. These experiments will help interpret the mechanism of action of this and formerly identified peptides as well as the future identification of new peptides. We also reveal structural determinants that make natural ICK peptides active against Nav1.1 challenging to synthesize. Altogether, the knowledge gained by this study will help facilitate the discovery and development of new compounds active on this critical ion channel target.

Keywords: Automated patch clamp; Biophysics; Cellular assay; Dravet disease; Drug discovery; High-throughput screening; JzTx-34; Lead optimization; Peptide synthesis; Pharmacology; Structural functional relationships; hNa(v)1.1 channel.

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Conflict of interest statement

Declaration of Competing Interest The authors declare the following financial interests/personal relationships which may be considered as potential competing interests: CC and RB are employee and CEO of Smartox Biotechnology, respectively. MDW is a founder and consultant of Smartox Biotechnology. KK, SL and JPJ are employees of Xenon Pharmaceuticals. CC is a past employee of Xenon Pharmaceuticals.

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