ArticleBritish journal of pharmacology2015
Seven novel modulators of the analgesic target NaV 1.7 uncovered using a high-throughput venom-based discovery approach.
Article in British journal of pharmacology, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 47 papers.
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Who cites it
47 citing papers in PubMed.
- Web of Potentials: Neuroactive Components of Spider Venom and Their Emerging Pharmacologic Applications in Neurologic Diseases.BioDrugs : clinical immunotherapeutics, biopharmaceuticals and gene therapy · 2026Review
- Refining the NaFEBS letters · 2025Article
- A High-Throughput Biosensing Approach for Rapid Screening of Compounds Targeting the hNav1.1 Channel: Marine Toxins as a Case Study.Marine drugs · 2025Article
- Optimizing Nav1.7-Targeted Analgesics: Revealing Off-Target Effects of Spider Venom-Derived Peptide Toxins and Engineering Strategies for Improvement.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Development and Validation of Nerve-Targeted Bacteriochlorin Sensors.Journal of the American Chemical Society · 2023Article
- General mechanism of spider toxin family I acting on sodium channel Nav1.7.Zoological research · 2022Article
- Pharmacological Dissection of the Crosstalk between NaInternational journal of molecular sciences · 2022Article
- From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma.Frontiers in molecular biosciences · 2022Review
- Voltage-Gated Sodium Channel Modulation by a New Spider Toxin Ssp1a Isolated From an Australian Theraphosid.Frontiers in pharmacology · 2021Article
- Peripheral Voltage-Gated Cation Channels in Neuropathic Pain and Their Potential as Therapeutic Targets.Frontiers in pain research (Lausanne, Switzerland) · 2021Review
- The Tarantula Venom Peptide Eo1a Binds to the Domain II S3-S4 Extracellular Loop of Voltage-Gated Sodium Channel NaFrontiers in pharmacology · 2021Article
- Pain-related toxins in scorpion and spider venoms: a face to face with ion channels.The journal of venomous animals and toxins including tropical diseases · 2021Review
- Engineering of a Spider PeptideFrontiers in molecular biosciences · 2021Article
- Fluorescence labeling of a NaEJNMMI research · 2020Article
- Addition of K22 Converts Spider Venom Peptide Pme2a from an Activator to an Inhibitor of NaBiomedicines · 2020Article
- Article
- Spider Knottin Pharmacology at Voltage-Gated Sodium Channels and Their Potential to Modulate Pain Pathways.Toxins · 2019Review
- Development of High-Throughput Fluorescent-Based Screens to Accelerate Discovery of P2X Inhibitors from Animal Venoms.Journal of natural products · 2019Article
- Evaluation of the Spider (Toxins · 2019Article
- Article
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Authors and funding
11 authors.
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Abstract
background and purposeChronic pain is a serious worldwide health issue, with current analgesics having limited efficacy and dose-limiting side effects. Humans with loss-of-function mutations in the voltage-gated sodium channel NaV 1.7 (hNaV 1.7) are indifferent to pain, making hNaV 1.7 a promising target for analgesic development. Since spider venoms are replete with NaV channel modulators, we examined their potential as a source of hNaV 1.7 inhibitors. EXPERIMENTAL APPROACH: We developed a high-throughput fluorescent-based assay to screen spider venoms against hNaV 1.7 and isolate 'hit' peptides. To examine the binding site of these peptides, we constructed a panel of chimeric channels in which the S3b-S4 paddle motif from each voltage sensor domain of hNaV 1.7 was transplanted into the homotetrameric KV 2.1 channel. KEY
resultsWe screened 205 spider venoms and found that 40% contain at least one inhibitor of hNaV 1.7. By deconvoluting 'hit' venoms, we discovered seven novel members of the NaSpTx family 1. One of these peptides, Hd1a (peptide μ-TRTX-Hd1a from venom of the spider Haplopelma doriae), inhibited hNaV 1.7 with a high level of selectivity over all other subtypes, except hNaV 1.1. We showed that Hd1a is a gating modifier that inhibits hNaV 1.7 by interacting with the S3b-S4 paddle motif in channel domain II. The structure of Hd1a, determined using heteronuclear NMR, contains an inhibitor cystine knot motif that is likely to confer high levels of chemical, thermal and biological stability. CONCLUSION AND IMPLICATIONS: Our data indicate that spider venoms are a rich natural source of hNaV 1.7 inhibitors that might be useful leads for the development of novel analgesics.
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