Huwentoxin-XVI, an analgesic, highly reversible mammalian N-type calcium channel antagonist from Chinese tarantula Ornithoctonus huwena

Deng, Mei; Luo, Xuan; Xiao, Yucheng; Sun, Zhenghua; Jiang, Liping; Z, Liu; Zeng, Xin; Chen, Hanchun; Tang, Jianhua; Zeng, Weimin; Liang, Songping

doi:10.1016/j.neuropharm.2014.01.017

Cited by 23 publications

(28 citation statements)

References 61 publications

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“…These can be attributed to the controversy surrounding the purported mechanism of action of gabapentin as studies report different mechanisms. 12,27,28,36,73 Recently, Huwentoxin-XVI, a toxin from the tarantula Ornithoctonus huwena, which inhibits N-type calcium channels, reduced postincision allodynia with a maximal effect at 2.5 hours 23 ; however, this should be used cautiously in humans because of potential toxicities.…”

Section: Discussionmentioning

confidence: 99%

A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors

François‐Moutal

Wang

Moutal

et al. 2015

Pain

115

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Targeting proteins within the N-type voltage-gated calcium channel (CaV2.2) complex has proven to be an effective strategy for developing novel pain therapeutics. We describe a novel peptide aptamer derived from the collapsin response mediator protein 2 (CRMP2), a CaV2.2-regulatory protein. Addition of a 14-carbon myristate group to the peptide (myr-tat-CBD3) tethered it to the membrane of primary sensory neurons near surface CaV2.2. Pull-down studies demonstrated that myr-tat-CBD3 peptide interfered with the CRMP2–CaV2.2 interaction. Quantitative confocal immunofluorescence revealed a pronounced reduction of CaV2.2 trafficking after myr-tat-CBD3 treatment and increased efficiency in disrupting CRMP2-CaV2.2 colocalization compared with peptide tat-CBD3. Consequently, myr-tat-CBD3 inhibited depolarization-induced calcium influx in sensory neurons. Voltage clamp electrophysiology experiments revealed a reduction of Ca2+, but not Na+, currents in sensory neurons after myr-tat-CBD3 exposure. Current clamp electrophysiology experiments demonstrated a reduction in excitability of small-diameter dorsal root ganglion neurons after exposure to myr-tat-CBD3. Myr-tat-CBD3 was effective in significantly attenuating carrageenan-induced thermal hypersensitivity and reversing thermal hypersensitivity induced by a surgical incision of the plantar surface of the rat hind paw, a model of postoperative pain. These effects are compared with those of tat-CBD3—the nonmyristoylated tat-conjugated CRMP2 peptide as well as scrambled versions of CBD3 and CBD3-lacking control peptides. Our results demonstrate that the myristoyl tag enhances intracellular delivery and local concentration of the CRMP2 peptide aptamer near membrane-delimited calcium channels resulting in pronounced interference with the calcium channel complex, superior suppression of calcium influx, and better antinociceptive potential.

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Section: Discussionmentioning

confidence: 99%

A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors

François‐Moutal

Wang

Moutal

et al. 2015

Pain

115

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“…Other components usually found in their venoms are nucleotides, free amino acids, neurotransmitters, polyamines and salts [1]. Due to the diverse mixture of components, tarantula venoms represent an important source of novel biologically active compounds that are potentially valuable for the development of therapeutic agents, tools for pharmacological research, and insecticidal peptides for potential use in agriculture [2–4]. …”

Section: Introductionmentioning

confidence: 99%

Pharmacological characterization of venoms from three theraphosid spiders: Poecilotheria regalis, Ceratogyrus darlingi and Brachypelma epicureanum

García-Arredondo¹,

Rodríguez-Rios²,

Díaz-Peña³

et al. 2015

J Venom Anim Toxins Incl Trop Dis

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BackgroundTarantulas (Theraphosidae) represent an important source of novel biologically active compounds that target a variety of ion channels and cell receptors in both insects and mammals. In this study, we evaluate and compare the pharmacological activity of venoms from three taxonomically different theraphosid spiders bred in captivity: Poecilotheria regalis, an aggressive arboreal tarantula from southeastern India; Ceratogyrus darlingi, an aggressive tarantula from southern Africa; and Brachypelma epicureanum, a docile tarantula from the Yucatan dry forest of Mexico. Prior to this study, no research had been conducted with regard to the composition and pharmacological activity of these venoms.MethodsThe pharmacological characterization of the venoms was described for the first time by the assessment of their toxicity in crickets (LD50) along with their nociceptive (by using the formalin test), hyaluronidase, phospholipase A2, edematogenic and caseinolytic activity.ResultsP. regalis and B. epicureanum venoms induced a similar lethal effect on crickets (LD50 = 5.23 ± 3.1 and 14.4 ± 5.0 μg protein/g 48 h post-injection, respectively), whereas C. darlingi venom (119.4 ± 29.5 μg protein/g 48 h post-injection) was significantly less lethal than the other two venoms. All three venoms induced similar edematogenic activity on rats but did not induce nociceptive behavior. The assessment of enzymatic activity indicated that P. regalis venom induces significantly higher hyaluronidase activity (27.6 ± 0.9 TRU/mg) than both C. darlingi (99.7 ± 1.9 TRU/mg) and B. epicureanum (99.6 ± 1.6 TRU/mg); these latter venoms did not display phospholipase A2 or caseinolytic activity.ConclusionsThis study demonstrates that these theraphosid spiders of different habitats produce venoms with different activities. P. regalis venom displays a high level of hyaluronidase activity, which may be associated with its potentially medically significant bite.

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“…An exception is HWTX-XVI (U 10 -TRTX-Hh1a), a 39-residue ICK toxin isolated from the venom of Chinese tarantula Haplopelma huwenum. HWTX-XVI blocks Ca V 2.2 currents in rat DRG neurons with an IC 50 of 60 nM, and channel block is rapidly reversible (τ off ∼ 66 s) [107]. In contrast, HWTX-XVI was shown to have no effect on TTX-s or TTX-r Na V channel currents in DRGs, or any of six Kv subtypes examined [107].…”

Section: Spider-venom Peptides That Modulate Ca V Channel Activitymentioning

confidence: 95%

“…HWTX-XVI proved to be highly analgesic in a variety of rodent pain models [107]. Intramuscular injection of HWTX-XVI (0.25 mg/kg) was as effective as morphine in reducing mechanical allodynia in a rat model of postoperative incisional pain.…”

Section: Spider-venom Peptides That Modulate Ca V Channel Activitymentioning

confidence: 95%

“…Of these, Ca v 2.1, Ca v 2.2 and Ca v 3 channels have been validated as analgesic targets [105,106]. Most studies have focused on Ca v 2.2, which is highly expressed in dorsal root ganglia (DRG) and central terminals of sensory neurons in the dorsal horn of the spinal cord [107]. ω-Conotoxin MVIIA, a cone-snail venom peptide that selectively blocks Ca V 2.2, is an FDA-approved drug sold under the trade name Prialt ® [108].…”

Section: Spider-venom Peptides That Modulate Ca V Channel Activitymentioning

confidence: 99%

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Spider Venomics: Implications for Drug Discovery

et al. 2014

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Over a period of more than 300 million years, spiders have evolved complex venoms containing an extraordinary array of toxins for prey capture and defense against predators. The major components of most spider venoms are small disulfide-bridged peptides that are highly stable and resistant to proteolytic degradation. Moreover, many of these peptides have high specificity and potency toward molecular targets of therapeutic importance. This unique combination of bioactivity and stability has made spider-venom peptides valuable both as pharmacological tools and as leads for drug development. This review describes recent advances in spider-venom-based drug discovery pipelines. We discuss spider-venom-derived peptides that are currently under investigation for treatment of a diverse range of pathologies including pain, stroke and cancer.

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Huwentoxin-XVI, an analgesic, highly reversible mammalian N-type calcium channel antagonist from Chinese tarantula Ornithoctonus huwena

Cited by 23 publications

References 61 publications

A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors

A membrane-delimited N-myristoylated CRMP2 peptide aptamer inhibits CaV2.2 trafficking and reverses inflammatory and postoperative pain behaviors

Pharmacological characterization of venoms from three theraphosid spiders: Poecilotheria regalis, Ceratogyrus darlingi and Brachypelma epicureanum

Spider Venomics: Implications for Drug Discovery

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