Next Article in Journal
Cytotoxic and Proapoptotic Activity of Sanguinarine, Berberine, and Extracts of Chelidonium majus L. and Berberis thunbergii DC. toward Hematopoietic Cancer Cell Lines
Next Article in Special Issue
Venomic, Transcriptomic, and Bioactivity Analyses of Pamphobeteus verdolaga Venom Reveal Complex Disulfide-Rich Peptides That Modulate Calcium Channels
Previous Article in Journal
A Spectroscopic Study on Secondary Structure and Thermal Unfolding of the Plant Toxin Gelonin Confirms Some Typical Structural Characteristics and Unravels the Sequence of Thermal Unfolding Events
Previous Article in Special Issue
Inhibition of Kv2.1 Potassium Channels by MiDCA1, A Pre-Synaptically Active PLA2-Type Toxin from Micrurus dumerilii carinicauda Coral Snake Venom
Open AccessArticle

Evaluation of the Spider (Phlogiellus genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates

Service d’Ingénierie Moléculaire des Protéines (SIMOPRO), CEA, Université Paris-Saclay, F-91191 Gif sur Yvette, France
Sanofi R&D, Integrated Drug Discovery—High Content Biology, F-94440 Vitry-sur-Seine, France
Institut de Génomique Fonctionnelle (IGF), CNRS-UMR 5203, Inserm-U661, Université de Montpellier, Laboratories of Excellence—Ion Channel Science and Therapeutics, F-34094 Montpellier, France
Institut des Neurosciences Paris-Saclay (Neuro-PSI), UMR CNRS/Université Paris-Sud 9197, Université Paris-Saclay, F-91198 Gif sur Yvette, France
Authors to whom correspondence should be addressed.
Toxins 2019, 11(9), 484;
Received: 11 July 2019 / Revised: 9 August 2019 / Accepted: 15 August 2019 / Published: 22 August 2019
(This article belongs to the Special Issue Venoms and Ion Channels)
Over the two last decades, venom toxins have been explored as alternatives to opioids to treat chronic debilitating pain. At present, approximately 20 potential analgesic toxins, mainly from spider venoms, are known to inhibit with high affinity the NaV1.7 subtype of voltage-gated sodium (NaV) channels, the most promising genetically validated antinociceptive target identified so far. The present study aimed to consolidate the development of phlotoxin 1 (PhlTx1), a 34-amino acid and 3-disulfide bridge peptide of a Phlogiellus genus spider, as an antinociceptive agent by improving its affinity and selectivity for the human (h) NaV1.7 subtype. The synthetic homologue of PhlTx1 was generated and equilibrated between two conformers on reverse-phase liquid chromatography and exhibited potent analgesic effects in a mouse model of NaV1.7-mediated pain. The effects of PhlTx1 and 8 successfully synthetized alanine-substituted variants were studied (by automated whole-cell patch-clamp electrophysiology) on cell lines stably overexpressing hNaV subtypes, as well as two cardiac targets, the hCaV1.2 and hKV11.1 subtypes of voltage-gated calcium (CaV) and potassium (KV) channels, respectively. PhlTx1 and D7A-PhlTx1 were shown to inhibit hNaV1.1–1.3 and 1.5–1.7 subtypes at hundred nanomolar concentrations, while their affinities for hNaV1.4 and 1.8, hCaV1.2 and hKV11.1 subtypes were over micromolar concentrations. Despite similar analgesic effects in the mouse model of NaV1.7-mediated pain and selectivity profiles, the affinity of D7A-PhlTx1 for the NaV1.7 subtype was at least five times higher than that of the wild-type peptide. Computational modelling was performed to deduce the 3D-structure of PhlTx1 and to suggest the amino acids involved in the efficiency of the molecule. In conclusion, the present structure–activity relationship study of PhlTx1 results in a low improved affinity of the molecule for the NaV1.7 subtype, but without any marked change in the molecule selectivity against the other studied ion channel subtypes. Further experiments are therefore necessary before considering the development of PhlTx1 or synthetic variants as antinociceptive drug candidates. View Full-Text
Keywords: Phlogiellus spider; phlotoxin 1; human voltage-gated ion channel subtypes; NaV1.7 channel subtype; mouse model of NaV1.7-mediated pain Phlogiellus spider; phlotoxin 1; human voltage-gated ion channel subtypes; NaV1.7 channel subtype; mouse model of NaV1.7-mediated pain
Show Figures

Figure 1

MDPI and ACS Style

Gonçalves, T.C.; Lesport, P.; Kuylle, S.; Stura, E.; Ciolek, J.; Mourier, G.; Servent, D.; Bourinet, E.; Benoit, E.; Gilles, N. Evaluation of the Spider (Phlogiellus genus) Phlotoxin 1 and Synthetic Variants as Antinociceptive Drug Candidates. Toxins 2019, 11, 484.

Show more citation formats Show less citations formats
Note that from the first issue of 2016, MDPI journals use article numbers instead of page numbers. See further details here.

Article Access Map by Country/Region

Search more from Scilit
Back to TopTop