Chemical synthesis, proper folding, nav channel selectivity profile and analgesic properties of the spider peptide phlotoxin 1

  • Phlotoxin-1 (PhlTx1) is a peptide previously identified in tarantula venom (Phlogius species) that belongs to the inhibitory cysteine-knot (ICK) toxin family. Like many ICK-based spider toxins, the synthesis of PhlTx1 appears particularly challenging, mostly for obtaining appropriate folding and concomitant suitable disulfide bridge formation. Herein, we describe a procedure for the chemical synthesis and the directed sequential disulfide bridge formation of PhlTx1 that allows for a straightforward production of this challenging peptide. We also performed extensive functional testing of PhlTx1 on 31 ion channel types and identified the voltage-gated sodium (Nav) channel Nav1.7 as the main target of this toxin. Moreover, we compared PhlTx1 activity to 10 other spider toxin activities on an automated patch-clamp system with Chinese Hamster Ovary (CHO) cells expressing human Nav1.7. Performing these analyses in reproducible conditions allowed for classification according to the potency of the best natural Nav1.7 peptide blockers. Finally, subsequent in vivo testing revealed that intrathecal injection of PhlTx1 reduces the response of mice to formalin in both the acute pain and inflammation phase without signs of neurotoxicity. PhlTx1 is thus an interesting toxin to investigate Nav1.7 involvement in cellular excitability and pain

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Author:Sébastien Nicolas, Claude Zoukimian, Frank Bosmans, Jérôme Montnach, Sylvie Diochot, Eva Cuypers, Stephan de Waard, Rémy Béroud, Dietrich MebsORCiDGND, David Craik, Didier Boturyn, Michel Lazdunski, Jan Tytgat, Michel de Waard
Parent Title (English):Toxins
Place of publication:Basel
Document Type:Article
Date of Publication (online):2019/06/21
Date of first Publication:2019/06/21
Publishing Institution:Universitätsbibliothek Johann Christian Senckenberg
Release Date:2020/05/13
Tag:Nav channel activity; Nav1.7; automated patch-clamp; directed disulfide bond formation; pain target; spider toxin
Page Number:21
Institutes:Medizin / Medizin
Dewey Decimal Classification:5 Naturwissenschaften und Mathematik / 57 Biowissenschaften; Biologie / 570 Biowissenschaften; Biologie
6 Technik, Medizin, angewandte Wissenschaften / 61 Medizin und Gesundheit / 610 Medizin und Gesundheit
Licence (German):License LogoCreative Commons - Namensnennung 4.0