Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1

Bibliographic Details
Title: Chemical Synthesis, Proper Folding, Nav Channel Selectivity Profile and Analgesic Properties of the Spider Peptide Phlotoxin 1
Authors: Sébastien Nicolas, Claude Zoukimian, Frank Bosmans, Jérôme Montnach, Sylvie Diochot, Eva Cuypers, Stephan De Waard, Rémy Béroud, Dietrich Mebs, David Craik, Didier Boturyn, Michel Lazdunski, Jan Tytgat, Michel De Waard
Source: Toxins, Vol 11, Iss 6, p 367 (2019)
Publisher Information: MDPI AG, 2019.
Publication Year: 2019
Collection: LCC:Medicine
Subject Terms: spider toxin, directed disulfide bond formation, Nav channel activity, Nav1.7, pain target, automated patch-clamp, Medicine
More Details: 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.
Document Type: article
File Description: electronic resource
Language: English
ISSN: 2072-6651
Relation: https://www.mdpi.com/2072-6651/11/6/367; https://doaj.org/toc/2072-6651
DOI: 10.3390/toxins11060367
Access URL: https://doaj.org/article/e86d22f9474449df85156f8c0d4cf8f5
Accession Number: edsdoj.86d22f9474449df85156f8c0d4cf8f5
Database: Directory of Open Access Journals
Full text is not displayed to guests.
More Details
ISSN:20726651
DOI:10.3390/toxins11060367
Published in:Toxins
Language:English