ArticleProceedings of the National Academy of Sciences of the United States of America2018
Mechanism-specific assay design facilitates the discovery of Nav1.7-selective inhibitors.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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Who cites it
18 citing papers in PubMed, 34 citations in OpenAlex.
- Targeting Supramolecular Active Complexes of NaAdvanced science (Weinheim, Baden-Wurttemberg, Germany) · 2026Article
- Molecular determinant of low-voltage dependence of human NaNature communications · 2026Article
- Sensory neuron-expressed FGF13 controls nociceptive signaling in diabetic neuropathy models.The Journal of clinical investigation · 2025Article
- Effects of NaCell biochemistry and biophysics · 2025Review
- A High-Throughput Biosensing Approach for Rapid Screening of Compounds Targeting the hNav1.1 Channel: Marine Toxins as a Case Study.Marine drugs · 2025Article
- Exploring the Potential of Bioactive Peptides: From Natural Sources to Therapeutics.International journal of molecular sciences · 2024Review
- Structural mapping of NaNature communications · 2023Article
- Phenotypic screening using waveform analysis of synchronized calcium oscillations in primary cortical cultures.PloS one · 2023Article
- Ectopic expression of Nav1.7 in spinal dorsal horn neurons induced by NGF contributes to neuropathic pain in a mouse spinal cord injury model.Frontiers in molecular neuroscience · 2023Article
- Reversal of Peripheral Neuropathic Pain by the Small-Molecule Natural Product Narirutin via Block of NaInternational journal of molecular sciences · 2022Article
- Screening an In-House Isoquinoline Alkaloids Library for New Blockers of Voltage-Gated NaMolecules (Basel, Switzerland) · 2022Article
- CaThe Journal of physiology · 2022Article
- High-throughput characterization of photocrosslinker-bearing ion channel variants to map residues critical for function and pharmacology.PLoS biology · 2021Article
- Status of peripheral sodium channel blockers for non-addictive pain treatment.Nature reviews. Neurology · 2020Review
- Conservation and divergence in NaChBac and NaScientific reports · 2020Article
- Lidocaine Binding Enhances Inhibition of Nav1.7 Channels by the Sulfonamide PF-05089771.Molecular pharmacology · 2020Article
- The voltage-gated sodium channel NaJournal of Cancer · 2019Article
- [Neuropathic pain syndromes and channelopathies].Der Internist · 2019Review
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Authors and funding
14 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Many ion channels, including Nav1.7, Cav1.3, and Kv1.3, are linked to human pathologies and are important therapeutic targets. To develop efficacious and safe drugs, subtype-selective modulation is essential, but has been extremely difficult to achieve. We postulate that this challenge is caused by the poor assay design, and investigate the Nav1.7 membrane potential assay, one of the most extensively employed screening assays in modern drug discovery. The assay uses veratridine to activate channels, and compounds are identified based on the inhibition of veratridine-evoked activities. We show that this assay is biased toward nonselective pore blockers and fails to detect the most potent, selective voltage-sensing domain 4 (VSD4) blockers, including PF-05089771 (PF-771) and GX-936. By eliminating a key binding site for pore blockers and replacing veratridine with a VSD-4 binding activator, we directed the assay toward non-pore-blocking mechanisms and discovered Nav1.7-selective chemical scaffolds. Hence, we address a major hurdle in Nav1.7 drug discovery, and this mechanistic approach to assay design is applicable to Cav3.1, Kv1.3, and many other ion channels to facilitate drug discovery.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.