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Computational design of peptides to target Na_V1.7 channel with high potency and selectivity for the treatment of pain.

ABSTRACT: The voltage-gated sodium Na_V1.7 channel plays a key role as a mediator of action potential propagation in C-fiber nociceptors and is an established molecular target for pain therapy. ProTx-II is a potent and moderately selective peptide toxin from tarantula venom that inhibits human Na_V1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human Na_V1.7 channels. Functional testing of designed peptides using electrophysiology identified the PTx2-3127 and PTx2-3258 peptides with IC₅₀s of 7 nM and 4 nM for hNa_V1.7 and more than 1000-fold selectivity over human Na_V1.1, Na_V1.3, Na_V1.4, Na_V1.5, Na_V1.8, and Na_V1.9 channels. PTx2-3127 inhibits Na_V1.7 currents in mouse and human sensory neurons and shows efficacy in rat models of chronic and thermal pain when administered intrathecally. Rationally designed peptide inhibitors of human Na_V1.7 channels have transformative potential to define a new class of biologics to treat pain.

SUBMITTER: Nguyen PT

PROVIDER: S-EPMC9831606 | biostudies-literature | 2022 Dec

REPOSITORIES: biostudies-literature

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Computational design of peptides to target NaV1.7 channel with high potency and selectivity for the treatment of pain.

Nguyen Phuong T PT Nguyen Hai M HM Wagner Karen M KM Stewart Robert G RG Singh Vikrant V Thapa Parashar P Chen Yi-Je YJ Lillya Mark W MW Ton Anh Tuan AT Kondo Richard R Ghetti Andre A Pennington Michael W MW Hammock Bruce B Griffith Theanne N TN Sack Jon T JT Wulff Heike H Yarov-Yarovoy Vladimir V

eLife 20221228

The voltage-gated sodium NaV1.7 channel plays a key role as a mediator of action potential propagation in C-fiber nociceptors and is an established molecular target for pain therapy. ProTx-II is a potent and moderately selective peptide toxin from tarantula venom that inhibits human NaV1.7 activation. Here we used available structural and experimental data to guide Rosetta design of potent and selective ProTx-II-based peptide inhibitors of human NaV1.7 channels. ...[more]

PMID: 36576241

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Project description:Huwentoxin-IV (HwTx-IV), a peptide discovered in the venom of the Chinese bird spider Cyriopagopus schmidti, has been reported to be a potent antinociceptive compound due to its action on the genetically-validated NaV1.7 pain target. Using this peptide for antinociceptive applications in vivo suffers from one major drawback, namely its negative impact on the neuromuscular system. Although studied only recently, this effect appears to be due to an interaction between the peptide and the NaV1.6 channel subtype located at the presynaptic level. The aim of this work was to investigate how HwTx-IV could be modified in order to alter the original human (h) NaV1.7/NaV1.6 selectivity ratio of 23. Nineteen HwTx-IV analogues were chemically synthesized and tested for their blocking effects on the Na+ currents flowing through these two channel subtypes stably expressed in cell lines. Dose-response curves for these analogues were generated, thanks to the use of an automated patch-clamp system. Several key amino acid positions were targeted owing to the information provided by earlier structure-activity relationship (SAR) studies. Among the analogues tested, the potency of HwTx-IV E4K was significantly improved for hNaV1.6, leading to a decreased hNaV1.7/hNaV1.6 selectivity ratio (close to 1). Similar decreased selectivity ratios, but with increased potency for both subtypes, were observed for HwTx-IV analogues that combine a substitution at position 4 with a modification of amino acid 1 or 26 (HwTx-IV E1G/E4G and HwTx-IV E4K/R26Q). In contrast, increased selectivity ratios (>46) were obtained if the E4K mutation was combined to an additional double substitution (R 26A/Y33W) or simply by further substituting the C-terminal amidation of the peptide by a carboxylated motif, linked to a marked loss of potency on hNaV1.6 in this latter case. These results demonstrate that it is possible to significantly modulate the selectivity ratio for these two channel subtypes in order to improve the potency of a given analogue for hNaV1.6 and/or hNaV1.7 subtypes. In addition, selective analogues for hNaV1.7, possessing better safety profiles, were produced to limit neuromuscular impairments.

Dataset Information

Computational design of peptides to target Na_V1.7 channel with high potency and selectivity for the treatment of pain.

Publications

Computational design of peptides to target Na<sub>V</sub>1.7 channel with high potency and selectivity for the treatment of pain.

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