ProTx-III, new selective Na_v1.7 blocker

ProTx-III (µ-TRTX-Tp1a; belongs to NaSpTx family 1) has been isolated from the venom of the Peruvian green-velvet tarantula Thrixopelma pruriens at the University of Queensland (Australia). ProTx-III has been described to be a selective inhibitor of Na_v1.7 with an IC50 value around 2 nM. The synthetic version of Tp1a produced by Smartox yields similar results in terms of Na_v1.7 inhibition (see Figure 1). Queensland scientists have described that ProTx-III induces no significant changes in the voltage dependence of activation or steady-state inactivation of Na_v1.7. ProTx-III also inhibits Na_v1.1, Na_v1.2 and Na_v1.6 at nanomolar concentrations and does not affects Cav channels and nicotinic acetylcholine receptors. ProTx-III demonstrates analgesic properties in vivo when injected intraplantary in mice prior treatment with OD1, an activator of Na_v1.7, which induces spontaneous pain.

Fig 1: effect of 5nM Smartox ProTx-III on hNav1.7 current studied by eliciting voltage steps from -60 to +40 mV at a holding potential of -90 mV.

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Description:

AA sequence:   Asp-Cys²-Leu-Lys-Phe-Gly-Trp-Lys-Cys⁹-Asn-Pro-Arg-Asn-Asp-Lys-Cys¹⁶-Cys¹⁷-Ser-Gly-Leu-Lys-Cys²²-Gly-Ser-Asn-His-Asn-Trp-Cys²⁹-Lys-Leu-His-Ile-NH₂Disulfide bonds:    Cys²-Cys¹⁷, Cys⁹-Cys²², Cys¹⁶-Cys²⁹Length (aa): 33Formula:      C₁₆₂H₂₄₆N₅₂O₄₃S₆Appearance: White lyophilized solidCAS number:Molecular Weight: 3802.47 DaSource: SyntheticSolubility: Water or saline buffer, 5 mg/mL maximum (recommendation)Counterion: TFA salts

Reference:

Identification and Characterization of ProTx-III

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.

Fernanda C., et al. (2015) Identification and Characterization of ProTx-III [m-TRTX-Tp1a], a New Voltage-Gated Sodium Channel Inhibitor from Venom of the Tarantula Thrixopelma pruriens. PMID: 25979003

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