ArticleProceedings of the National Academy of Sciences of the United States of America2016
Mutant cycle analysis with modified saxitoxins reveals specific interactions critical to attaining high-affinity inhibition of hNaV1.7.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 30 papers.
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Who cites it
30 citing papers in PubMed, 60 citations in OpenAlex.
- A designer saxitoxin-engineered sodium channel pair as a general tool for subtype-selective inhibition.Cell chemical biology · 2026Article
- Saxiphilin is a broad-spectrum toxin sponge for C13-modified saxitoxins.Structure (London, England : 1993) · 2026Article
- Saxiphilin functions as a toxin sponge protein that counteracts the effects of saxitoxin poisoning.Nature communications · 2026Article
- Saxiphilin is a broad-spectrum toxin sponge for C13-modified saxitoxins.bioRxiv : the preprint server for biology · 2026Article
- Saxiphilin functions as a 'toxin sponge' protein that counteracts the effects of saxitoxin poisoning.bioRxiv : the preprint server for biology · 2025Article
- A chemogenetic ligand-receptor pair for voltage-gated sodium channel subtype-selective inhibition.bioRxiv : the preprint server for biology · 2025Article
- Article
- The Chemistry and Biology of the Tetrodotoxin Natural Product Family.Angewandte Chemie (International ed. in English) · 2025Review
- Marine-derived bioactive compounds for neuropathic pain: pharmacology and therapeutic potential.Naunyn-Schmiedeberg's archives of pharmacology · 2025Review
- Voltage-gated sodium channels in excitable cells as drug targets.Nature reviews. Drug discovery · 2025Review
- Structural basis for saxitoxin congener binding and neutralization by anuran saxiphilins.Nature communications · 2025Article
- The Art and Science of Molecular Docking.Annual review of biochemistry · 2024Review
- Double and triple thermodynamic mutant cycles reveal the basis for specific MsbA-lipid interactions.eLife · 2024Article
- Toward high-resolution modeling of small molecule-ion channel interactions.Frontiers in pharmacology · 2024Article
- Trifunctional Saxitoxin Conjugates for Covalent Labeling of Voltage-Gated Sodium Channels.Chembiochem : a European journal of chemical biology · 2023Article
- Double and triple thermodynamic mutant cycles reveal the basis for specific MsbA-lipid interactions.bioRxiv : the preprint server for biology · 2023Article
- Discovery of Selective Inhibitors of NaACS medicinal chemistry letters · 2022Article
- Definition of a saxitoxin (STX) binding code enables discovery and characterization of the anuran saxiphilin family.Proceedings of the National Academy of Sciences of the United States of America · 2022Article
- General mechanism of spider toxin family I acting on sodium channel Nav1.7.Zoological research · 2022Article
- Druggability of Voltage-Gated Sodium Channels-Exploring Old and New Drug Receptor Sites.Frontiers in pharmacology · 2022Review
Corrections and comments
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Authors and funding
2 authors at 1 institution in 1 country.
Funding
Abstract
Improper function of voltage-gated sodium channels (NaVs), obligatory membrane proteins for bioelectrical signaling, has been linked to a number of human pathologies. Small-molecule agents that target NaVs hold considerable promise for treatment of chronic disease. Absent a comprehensive understanding of channel structure, the challenge of designing selective agents to modulate the activity of NaV subtypes is formidable. We have endeavored to gain insight into the 3D architecture of the outer vestibule of NaV through a systematic structure-activity relationship (SAR) study involving the bis-guanidinium toxin saxitoxin (STX), modified saxitoxins, and protein mutagenesis. Mutant cycle analysis has led to the identification of an acetylated variant of STX with unprecedented, low-nanomolar affinity for human NaV1.7 (hNaV1.7), a channel subtype that has been implicated in pain perception. A revised toxin-receptor binding model is presented, which is consistent with the large body of SAR data that we have obtained. This new model is expected to facilitate subsequent efforts to design isoform-selective NaV inhibitors.
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Registered trials
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.