Synthetic Analogues of Huwentoxin-IV Spider Peptide With Altered Human Na V 1.7/Na V 1.6 Selectivity Ratios.

Autor:	Lopez L; L'institut du Thorax, INSERM, CNRS, UNIV NANTES, Nantes, France., Montnach J; L'institut du Thorax, INSERM, CNRS, UNIV NANTES, Nantes, France., Oliveira-Mendes B; L'institut du Thorax, INSERM, CNRS, UNIV NANTES, Nantes, France., Khakh K; Xenon Pharmaceuticals, Burnaby, BC, Canada., Thomas B; Smartox Biotechnology, Saint-Egrève, France., Lin S; Xenon Pharmaceuticals, Burnaby, BC, Canada., Caumes C; Smartox Biotechnology, Saint-Egrève, France., Wesolowski S; Xenon Pharmaceuticals, Burnaby, BC, Canada., Nicolas S; L'institut du Thorax, INSERM, CNRS, UNIV NANTES, Nantes, France., Servent D; Département Médicaments et Technologies pour La Santé (DMTS), Service d'Ingénierie Moléculaire pour La Santé (SIMoS), ERL CNRS/CEA, Institut des Sciences du Vivant Frédéric Joliot, CEA, Université Paris Saclay, Gif-sur-Yvette, France., Cohen C; Xenon Pharmaceuticals, Burnaby, BC, Canada., Béroud R; Smartox Biotechnology, Saint-Egrève, France., Benoit E; Département Médicaments et Technologies pour La Santé (DMTS), Service d'Ingénierie Moléculaire pour La Santé (SIMoS), ERL CNRS/CEA, Institut des Sciences du Vivant Frédéric Joliot, CEA, Université Paris Saclay, Gif-sur-Yvette, France., De Waard M; L'institut du Thorax, INSERM, CNRS, UNIV NANTES, Nantes, France.; Smartox Biotechnology, Saint-Egrève, France.; LabEx « Ion Channels, Science and Therapeutics », Valbonne, France.
Jazyk:	angličtina
Zdroj:	Frontiers in cell and developmental biology [Front Cell Dev Biol] 2021 Dec 20; Vol. 9, pp. 798588. Date of Electronic Publication: 2021 Dec 20 (Print Publication: 2021).
DOI:	10.3389/fcell.2021.798588
Abstrakt:	Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider Cyriopagopus schmidti , has been reported to be a potent antinociceptive compound due to its action on the genetically-validated Na V 1.7 pain target. Using this peptide for antinociceptive applications in vivo suffers from one major drawback, namely its negative impact on the neuromuscular system. Although studied only recently, this effect appears to be due to an interaction between the peptide and the Na V 1.6 channel subtype located at the presynaptic level. The aim of this work was to investigate how HwTx-IV could be modified in order to alter the original human (h) Na V 1.7/Na V 1.6 selectivity ratio of 23. Nineteen HwTx-IV analogues were chemically synthesized and tested for their blocking effects on the Na + currents flowing through these two channel subtypes stably expressed in cell lines. Dose-response curves for these analogues were generated, thanks to the use of an automated patch-clamp system. Several key amino acid positions were targeted owing to the information provided by earlier structure-activity relationship (SAR) studies. Among the analogues tested, the potency of HwTx-IV E 4 K was significantly improved for hNa V 1.6, leading to a decreased hNa V 1.7/hNa V 1.6 selectivity ratio (close to 1). Similar decreased selectivity ratios, but with increased potency for both subtypes, were observed for HwTx-IV analogues that combine a substitution at position 4 with a modification of amino acid 1 or 26 (HwTx-IV E 1 G/E 4 G and HwTx-IV E 4 K/R 26 Q). In contrast, increased selectivity ratios (>46) were obtained if the E 4 K mutation was combined to an additional double substitution ( R 26 A/Y 33 W) or simply by further substituting the C-terminal amidation of the peptide by a carboxylated motif, linked to a marked loss of potency on hNa V 1.6 in this latter case. These results demonstrate that it is possible to significantly modulate the selectivity ratio for these two channel subtypes in order to improve the potency of a given analogue for hNa V 1.6 and/or hNa V 1.7 subtypes. In addition, selective analogues for hNa V 1.7, possessing better safety profiles, were produced to limit neuromuscular impairments. Competing Interests: Authors KK, SL, SW, and CC were employed by company Xenon Pharmaceuticals. Authors BT, CC, RB, and LL were employed by company Smartox Biotechnology. MDW is a consultant and founder of Smartox Biotechnology. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. (Copyright © 2021 Lopez, Montnach, Oliveira-Mendes, Khakh, Thomas, Lin, Caumes, Wesolowski, Nicolas, Servent, Cohen, Béroud, Benoit and De Waard.)
Databáze:	MEDLINE
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