Phoneutria toxin PnTx3-5 inhibits TRPV1 channel with antinociceptive action in an orofacial pain model

Pereira, Elizete Maria Rita; Souza, Jéssica M. de; Carobin, Natália Virtude; Silva, Juliana Figueira; Santos, Duana Carvalho; Júnior, Cláudio Antonio Silva; Binda, Nancy Scardua; Borges, Márcia Helena; Nagem, Ronaldo Alves Pinto; Kushmerick, Christopher; Ferreira, Juliano; Castro, Célio José de; Ribeiro, Fabíola M.; Gomez, Marcus V.

doi:10.1016/j.neuropharm.2019.107826

Cited by 10 publications

(5 citation statements)

References 41 publications

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“…Gomez and C. Castro-Junior (Faculdade Santa Casa de Belo Horizonte, Brazil), especially the toxin named Ph-α-1ß. This toxin interacts with different Ca 2+ channels and shows efficacy in many models of nociception, such as in cancer, fibromyalgia, pancreatitis, postoperative pain, diabetic neuropathic pain, and orofacial pain ( Da Silva Junior et al, 2020 ; Rita Pereira et al, 2020 ; Tonello et al, 2020 ; Aoki et al, 2021 ; Garcia Mendes et al, 2021 ). Another fraction from the venom of P. nigriventer , called PhTx4 ( Figure 1 ) was described having several insect toxins (for review see De Lima et al, 2016 ; Peigneur et al, 2018 ) targeting mainly Na + channels of insects ( De Lima et al, 2002 ; De Lima et al, 2007 ).…”

Section: Pain and The Antinociceptive Effect Of Pnpp-19mentioning

confidence: 99%

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

Silva

Nunes

Dourado

et al. 2022

Front. Mol. Biosci.

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The venom of the “armed” spider Phoneutria nigriventer comprises several potent toxins. One of the most toxic components from this venom is the neurotoxin PnTx2-6 (LD50 = ∼ 0.7 μg/mouse, 48 residues, five disulfide bridges, MW = 5,289.31 Da), which slows down the inactivation of various Na+ channels. In mice and rats, this toxin causes priapism, an involuntary and painful erection, similar to what is observed in humans bitten by P. nigriventer. While not completely elucidated, it is clear that PnTx2-6 potentiates erectile function via NO/cGMP signaling, but it has many off-target effects. Seeking to obtain a simpler and less toxic molecule able to retain the pharmacological properties of this toxin, we designed and synthesized the peptide PnPP-19 (19 residues, MW = 2,485.6 Da), representing a discontinuous epitope of PnTx2-6. This synthetic peptide also potentiates erectile function via NO/cGMP, but it does not target Na+ channels, and therefore, it displays nontoxic properties in animals even at high doses. PnPP-19 effectively potentiates erectile function not only after subcutaneous or intravenous administration but also following topical application. Surprisingly, PnPP-19 showed central and peripheral antinociceptive activity involving the opioid and cannabinoid systems, suggesting applicability in nociception. Furthermore, considering that PnPP-19 increases NO availability in the corpus cavernosum, this peptide was also tested in a model of induced intraocular hypertension, characterized by low NO levels, and it showed promising results by decreasing the intraocular pressure which prevents retinal damage. Herein, we discuss how was engineered this smaller active non-toxic peptide with promising results in the treatment of erectile dysfunction, nociception, and glaucoma from the noxious PnTx2-6, as well as the pitfalls of this ongoing journey.

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Section: Pain and The Antinociceptive Effect Of Pnpp-19mentioning

confidence: 99%

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

Silva

Nunes

Dourado

et al. 2022

Front. Mol. Biosci.

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“…PnTx3-3 and PnTx3-4 inhibit calcium influx [40], exocytosis, and glutamate release in synaptosomes [41,42]. Besides, it has been shown that PnTx3-6 and Tx3-5 can induce analgesic effects and are efficient in the treatment of persistent pathological pain [43][44][45][46][47].…”

Section: Visual Abstractmentioning

confidence: 99%

Comparative venomic profiles of three spiders of the genus Phoneutria

Fernandes

Moraes

Santos

et al. 2022

J. Venom. Anim. Toxins incl. Trop. Dis

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Background: Spider venoms induce different physio-pharmacological effects by binding with high affinity on molecular targets, therefore being of biotechnological interest. Some of these toxins, acting on different types of ion channels, have been identified in the venom of spiders of the genus Phoneutria, mainly from P. nigriventer. In spite of the pharmaceutical potential demonstrated by P. nigriventer toxins, there is limited information on molecules from venoms of the same genus, as their toxins remain poorly characterized. Understanding this diversity and clarifying the differences in the mechanisms of action of spider toxins is of great importance for establishing their true biotechnological potential. This prompted us to compare three different venoms of the Phoneutria genus: P. nigriventer (Pn-V), P. eickstedtae (Pe-V) and P. pertyi (Pp-V). Methods: Biochemical and functional comparison of the venoms were carried out by SDS-PAGE, HPLC, mass spectrometry, enzymatic activities and electrophysiological assays (whole-cell patch clamp). Results: The employed approach revealed that all three venoms had an overall similarity in their components, with only minor differences. The presence of a high number of similar proteins was evident, particularly toxins in the mass range of ~6.0 kDa. Hyaluronidase and proteolytic activities were detected in all venoms, in addition to isoforms of the toxins Tx1 and Tx2-6. All Tx1 isoforms blocked Nav1.6 ion currents, with slight differences. Conclusion: Our findings showed that Pn-V, Pe-V and Pp-V are highly similar concerning protein composition and enzymatic activities, containing isoforms of the same toxins sharing high sequence homology, with minor modifications. However, these structural and functional variations are very important for venom diversity. In addition, our findings will contribute to the comprehension of the molecular diversity of the venoms of the other species from Phoneutria genus, exposing their biotechnological potential as a source for searching for new active molecules.

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“…Another Phoneutria peptide, Tx3-5 (U7-CNTX-Pn1a) was recently characterized as a specific and potent inhibitor of TRPV1 channels without effect on TRPA1 [ 298 ]. Tx3-5 presents interesting analgesic properties in various mouse pain models.…”

Section: Spider Toxins Interacting With Pain-related Ion Channelsmentioning

confidence: 99%

“…Tx3-5 presents interesting analgesic properties in various mouse pain models. First, local injection of Tx3-5 (100 fmol, id ) prevents the nociceptive behavior induced by capsaicin injection into a rat left vibrissa in an orofacial test [ 298 ]. This local antinociceptive effect can be easily attributed to its blocking effect on TRPV1.…”

Section: Spider Toxins Interacting With Pain-related Ion Channelsmentioning

confidence: 99%

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

Diochot

2021

J. Venom. Anim. Toxins incl. Trop. Dis

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Pain is a common symptom induced during envenomation by spiders and scorpions. Toxins isolated from their venom have become essential tools for studying the functioning and physiopathological role of ion channels, as they modulate their activity. In particular, toxins that induce pain relief effects can serve as a molecular basis for the development of future analgesics in humans. This review provides a summary of the different scorpion and spider toxins that directly interact with pain-related ion channels, with inhibitory or stimulatory effects. Some of these toxins were shown to affect pain modalities in different animal models providing information on the role played by these channels in the pain process. The close interaction of certain gating-modifier toxins with membrane phospholipids close to ion channels is examined along with molecular approaches to improve selectivity, affinity or bioavailability in vivo for therapeutic purposes.

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Phoneutria toxin PnTx3-5 inhibits TRPV1 channel with antinociceptive action in an orofacial pain model

Cited by 10 publications

References 41 publications

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

From the PnTx2-6 Toxin to the PnPP-19 Engineered Peptide: Therapeutic Potential in Erectile Dysfunction, Nociception, and Glaucoma

Comparative venomic profiles of three spiders of the genus Phoneutria

Pain-related toxins in scorpion and spider venoms: a face to face with ion channels

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