PnPP-19 Peptide as a Novel Drug Candidate for Topical Glaucoma Therapy Through Nitric Oxide Release

Silva, Carolina Nunes da; Dourado, Lays Fernanda Nunes; Lima, Maria Elena de; Silva-Cunha, Armando

doi:10.1167/tvst.9.8.33

Cited by 14 publications

(9 citation statements)

References 38 publications

(79 reference statements)

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“…As a NO-inducer peptide, PnPP-19 was able to reduce IOP in rats healthy or with ocular hypertension for 24 h after a single dose (eye drop), without toxicity. Besides, it promoted neuroprotection by preventing the progression of optic nerve degeneration ( Silva et al, 2020 ). These results highlight its potential as a drug for the treatment of glaucoma and other neurodegenerative eye diseases.…”

Section: Discussionmentioning

confidence: 99%

“…Histological analysis showed significant loss of RGC in eyes of rat treated with vehicle. However, in the group treated with PnPP-19, the number of RGC was similar to the healthy eyes, suggesting that treatment with PnPP-19 was able to protect these cells ( Silva et al, 2020 ) ( Figure 4 ).…”

Section: Hypotensive and Neuroprotective Effects Of Pnpp-19 In The Eyesmentioning

confidence: 90%

“…Aiming to verify potential ocular use of PnPP-19, the irritant potential of this peptide was evaluated in the eye by using the Hen’s egg test in the chorioallantoic membrane (HET-CAM), and the ocular irritation index was calculated ( Silva et al, 2020 ). Only the positive control was classified as severely irritating, the negative control and the different concentrations of PnPP-19 tested showed no signs of toxicity.…”

Section: Hypotensive and Neuroprotective Effects Of Pnpp-19 In The Eyesmentioning

confidence: 99%

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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: Discussionmentioning

confidence: 99%

Section: Hypotensive and Neuroprotective Effects Of Pnpp-19 In The Eyesmentioning

confidence: 90%

Section: Hypotensive and Neuroprotective Effects Of Pnpp-19 In The Eyesmentioning

confidence: 99%

See 1 more Smart Citation

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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“…Some toxins that act on different types of ion channels, with the considerable advantage of binding selectively, have been identified in the venom of the spider P. nigriventer [ 17 ]. Possibilities for the development of new drugs based on these toxins, as well as their use for a deeper understanding of complex physiological processes, have been described[ 35 , 36 , 50 , 51 , 63 ].…”

Section: Discussionmentioning

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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“…The dynamics of ERG signals vary in people with various conditions and can therefore aid in differentiating individuals with glaucoma (Grillo et al, 2018 ), schizophrenia (Demmin et al, 2018 ), obesity (Yapici et al, 2021 ), and bipolar disorder (Hébert et al, 2020 ). ERG can also help in evaluating the effectiveness of new or existing drugs and therapy modalities (Lai et al, 2006 , 2009 ; Nebbioso et al, 2009 ; da Silva et al, 2020 ).…”

Section: Methodsmentioning

confidence: 99%

Novel Machine-Learning Based Framework Using Electroretinography Data for the Detection of Early-Stage Glaucoma

et al. 2022

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PurposeEarly-stage glaucoma diagnosis has been a challenging problem in ophthalmology. The current state-of-the-art glaucoma diagnosis techniques do not completely leverage the functional measures' such as electroretinogram's immense potential; instead, focus is on structural measures like optical coherence tomography. The current study aims to take a foundational step toward the development of a novel and reliable predictive framework for early detection of glaucoma using machine-learning-based algorithm capable of leveraging medically relevant information that ERG signals contain.MethodsERG signals from 60 eyes of DBA/2 mice were grouped for binary classification based on age. The signals were also grouped based on intraocular pressure (IOP) for multiclass classification. Statistical and wavelet-based features were engineered and extracted. Important predictors (ERG tests and features) were determined, and the performance of five machine learning-based methods were evaluated.ResultsRandom forest (bagged trees) ensemble classifier provided the best performance in both binary and multiclass classification of ERG signals. An accuracy of 91.7 and 80% was achieved for binary and multiclass classification, respectively, suggesting that machine-learning-based models can detect subtle changes in ERG signals if trained using advanced features such as those based on wavelet analyses.ConclusionsThe present study describes a novel, machine-learning-based method to analyze ERG signals providing additional information that may be used to detect early-stage glaucoma. Based on promising performance metrics obtained using the proposed machine-learning-based framework leveraging an established ERG data set, we conclude that the novel framework allows for detection of functional deficits of early/various stages of glaucoma in mice.

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PnPP-19 Peptide as a Novel Drug Candidate for Topical Glaucoma Therapy Through Nitric Oxide Release

Abstract: PnPP-19 peptide as a novel drug candidate for topical glaucoma therapy through nitric oxide release.

Cited by 14 publications

References 38 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

Novel Machine-Learning Based Framework Using Electroretinography Data for the Detection of Early-Stage Glaucoma

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