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Molecular Pharmacology

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Research ArticleArticle

Identification and Characterization of ProTx-III [μ-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens

Fernanda C. Cardoso, Zoltan Dekan, K. Johan Rosengren, Andelain Erickson, Irina Vetter, Jennifer R. Deuis, Volker Herzig, Paul F. Alewood, Glenn F. King and Richard J. Lewis
Molecular Pharmacology August 2015, 88 (2) 291-303; DOI: https://doi.org/10.1124/mol.115.098178
Fernanda C. Cardoso
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Zoltan Dekan
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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K. Johan Rosengren
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Andelain Erickson
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Irina Vetter
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Jennifer R. Deuis
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Volker Herzig
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Paul F. Alewood
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Glenn F. King
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Richard J. Lewis
Institute for Molecular Bioscience (F.C.C., Z.D., I.V., J.R.D., V.H., P.F.A., G.F.K., R.J.L.), School of Biomedical Sciences (K.J.R.), and School of Chemistry and Molecular Biosciences (A.E.), The University of Queensland, Brisbane, Queensland, Australia
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Abstract

Spider venoms are a rich source of ion channel modulators with therapeutic potential. Given the analgesic potential of subtype-selective inhibitors of voltage-gated sodium (NaV) channels, we screened spider venoms for inhibitors of human NaV1.7 (hNaV1.7) using a high-throughput fluorescent assay. Here, we describe the discovery of a novel NaV1.7 inhibitor, μ-TRTX-Tp1a (Tp1a), isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens. Recombinant and synthetic forms of this 33-residue peptide preferentially inhibited hNaV1.7 > hNaV1.6 > hNaV1.2 > hNaV1.1 > hNaV1.3 channels in fluorescent assays. NaV1.7 inhibition was diminished (IC50 11.5 nM) and the association rate decreased for the C-terminal acid form of Tp1a compared with the native amidated form (IC50 2.1 nM), suggesting that the peptide C terminus contributes to its interaction with hNaV1.7. Tp1a had no effect on human voltage-gated calcium channels or nicotinic acetylcholine receptors at 5 μM. Unlike most spider toxins that modulate NaV channels, Tp1a inhibited hNaV1.7 without significantly altering the voltage dependence of activation or inactivation. Tp1a proved to be analgesic by reversing spontaneous pain induced in mice by intraplantar injection in OD1, a scorpion toxin that potentiates hNaV1.7. The structure of Tp1a as determined using NMR spectroscopy revealed a classic inhibitor cystine knot (ICK) motif. The molecular surface of Tp1a presents a hydrophobic patch surrounded by positively charged residues, with subtle differences from other ICK spider toxins that might contribute to its different pharmacological profile. Tp1a may help guide the development of more selective and potent hNaV1.7 inhibitors for treatment of chronic pain.

Footnotes

    • Received February 2, 2015.
    • Accepted May 15, 2015.
  • This work was supported by the Australian Research Council Discovery Project [Grant DP110103129], Linkage Project [Grant LP130101143], Future Fellowships to K.J.R. and I.V., and the Australian National Health and Medical Research Council Principal Research Fellowships to R.J.L., G.F.K., and P.A. The Australian Proteome Analysis Facility is supported under the Australian Government’s National Collaborative Research Infrastructure Strategy.

  • dx.doi.org/10.1124/mol.115.098178.

  • Copyright © 2015 by The American Society for Pharmacology and Experimental Therapeutics
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Molecular Pharmacology: 88 (2)
Molecular Pharmacology
Vol. 88, Issue 2
1 Aug 2015
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Research ArticleArticle

New Sodium Channel Inhibitor from Thrixopelma pruriens

Fernanda C. Cardoso, Zoltan Dekan, K. Johan Rosengren, Andelain Erickson, Irina Vetter, Jennifer R. Deuis, Volker Herzig, Paul F. Alewood, Glenn F. King and Richard J. Lewis
Molecular Pharmacology August 1, 2015, 88 (2) 291-303; DOI: https://doi.org/10.1124/mol.115.098178

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Research ArticleArticle

New Sodium Channel Inhibitor from Thrixopelma pruriens

Fernanda C. Cardoso, Zoltan Dekan, K. Johan Rosengren, Andelain Erickson, Irina Vetter, Jennifer R. Deuis, Volker Herzig, Paul F. Alewood, Glenn F. King and Richard J. Lewis
Molecular Pharmacology August 1, 2015, 88 (2) 291-303; DOI: https://doi.org/10.1124/mol.115.098178
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