ArticlePloS one2018
Pharmacological characterization of potent and selective NaV1.7 inhibitors engineered from Chilobrachys jingzhao tarantula venom peptide JzTx-V.
Article in PloS one, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 25 papers.
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Who cites it
25 citing papers in PubMed, 49 citations in OpenAlex.
- Refining the NaFEBS letters · 2025Article
- Functional effects of drugs and toxins interacting with NaFrontiers in pharmacology · 2024Review
- Computational design of peptides to target NaeLife · 2022Article
- Chemical and Biological Tools for the Study of Voltage-Gated Sodium Channels in Electrogenesis and Nociception.Chembiochem : a European journal of chemical biology · 2022Review
- Towards Structure-Guided Development of Pain Therapeutics Targeting Voltage-Gated Sodium Channels.Frontiers in pharmacology · 2022Review
- Selective Targeting of Nav1.7 with Engineered Spider Venom-Based Peptides.Channels (Austin, Tex.) · 2021Review
- Scalable Biosynthetic Production of Knotted Peptides Enables ADME and Thermodynamic Folding Studies.ACS omega · 2021Article
- Venom-Derived Peptides Inhibiting Voltage-Gated Sodium and Calcium Channels in Mammalian Sensory Neurons.Advances in experimental medicine and biology · 2021Article
- Mechanisms Underlying Gastrodin Alleviating Vincristine-Induced Peripheral Neuropathic Pain.Frontiers 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
- Status of peripheral sodium channel blockers for non-addictive pain treatment.Nature reviews. Neurology · 2020Review
- Article
- Discovery of a selective, state-independent inhibitor of NaScientific reports · 2020Article
- Mapping the Molecular Surface of the Analgesic NaACS pharmacology & translational science · 2020Article
- Manipulation of a spider peptide toxin alters its affinity for lipid bilayers and potency and selectivity for voltage-gated sodium channel subtype 1.7.The Journal of biological chemistry · 2020Article
- Article
- A Chemical Biology Approach to Probing the Folding Pathways of the Inhibitory Cystine Knot (ICK) Peptide ProTx-II.Frontiers in chemistry · 2020Article
- Article
- Antibodies and venom peptides: new modalities for ion channels.Nature reviews. Drug discovery · 2019Review
- From identification to functional characterization of cyriotoxin-1a, an antinociceptive toxin from the spider Cyriopagopus schioedtei.British journal of pharmacology · 2019Article
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Authors and funding
18 authors at 2 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Identification of voltage-gated sodium channel NaV1.7 inhibitors for chronic pain therapeutic development is an area of vigorous pursuit. In an effort to identify more potent leads compared to our previously reported GpTx-1 peptide series, electrophysiology screening of fractionated tarantula venom discovered the NaV1.7 inhibitory peptide JzTx-V from the Chinese earth tiger tarantula Chilobrachys jingzhao. The parent peptide displayed nominal selectivity over the skeletal muscle NaV1.4 channel. Attribute-based positional scan analoging identified a key Ile28Glu mutation that improved NaV1.4 selectivity over 100-fold, and further optimization yielded the potent and selective peptide leads AM-8145 and AM-0422. NMR analyses revealed that the Ile28Glu substitution changed peptide conformation, pointing to a structural rationale for the selectivity gains. AM-8145 and AM-0422 as well as GpTx-1 and HwTx-IV competed for ProTx-II binding in HEK293 cells expressing human NaV1.7, suggesting that these NaV1.7 inhibitory peptides interact with a similar binding site. AM-8145 potently blocked native tetrodotoxin-sensitive (TTX-S) channels in mouse dorsal root ganglia (DRG) neurons, exhibited 30- to 120-fold selectivity over other human TTX-S channels and exhibited over 1,000-fold selectivity over other human tetrodotoxin-resistant (TTX-R) channels. Leveraging NaV1.7-NaV1.5 chimeras containing various voltage-sensor and pore regions, AM-8145 mapped to the second voltage-sensor domain of NaV1.7. AM-0422, but not the inactive peptide analog AM-8374, dose-dependently blocked capsaicin-induced DRG neuron action potential firing using a multi-electrode array readout and mechanically-induced C-fiber spiking in a saphenous skin-nerve preparation. Collectively, AM-8145 and AM-0422 represent potent, new engineered NaV1.7 inhibitory peptides derived from the JzTx-V scaffold with improved NaV selectivity and biological activity in blocking action potential firing in both DRG neurons and C-fibers.
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