The synthetic peptide PnPP-19 potentiates erectile function via nNOS and iNOS

Silva, Carolina Nunes da; Pedrosa, Kenia Nunes; Silva, Grazielle C.; Cunha, Pricila da Silva; Diniz, Thiago F.; Maia, Luísa Michette S.; Almeida, Flávia De Marco; Gomez, Ricardo Santiago; Lemos, Virgı́nia S.; Gomes, Dawidson Assis; Lima, Maria Elena de

doi:10.1016/j.niox.2021.04.007

Cited by 4 publications

(9 citation statements)

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“…In contrast, no changes were observed in the activation site Ser1177 and deactivation site Thr495 of eNOS. These findings are corroborated by using knockout mice for both eNOS and nNOS enzymes ( Silva et al, 2021 ). Treatment with PnPP-19 not only strongly induced gene expression for iNos but also significantly elevated its expression following EFS.…”

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 74%

“…It is easily synthesized, does not have disulfide bridges, is stable, and it potentiates murine erectile function, inducing irrelevant immunogenicity and no evident signs of toxicity ( Silva et al, 2015 ). Surprisingly, PnPP-19 did not act on Na v channels as its toxin precursor, and does not affect the heart of rats, but it acted by modulating the expression of NOS enzymes in CC ( Silva et al, 2015 , 2021 ). The mode of action of PnPP-19 is different in relation to the current pharmacotherapy since it increases the production of NO/cGMP and has a synergistic, or additive effect with PDE-5 inhibitors.…”

Section: Discussionmentioning

confidence: 95%

“…N6-(1-iminoethyl)-L-lysine dihydrochloride (L-NIL), a specific blocker of the iNOS enzyme, suppressed the effect of PnPP-19 on erectile function. The knockout mice for iNOS showed no relaxation in their cavernous strips, which was surprisingly significantly less than that observed for control strips (iNOS KO + vehicle) ( Silva et al, 2021 ). This study highlights the importance of the iNOS enzyme in the erectogenic mechanism, which is corroborated by Hung et al using cavernosal smooth muscle cell cultures ( Hung et al, 1995 ).…”

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 95%

“…Both effects were blocked by a non-selective NOS inhibitor (L-NAME) and partially reduced by 7-nitroindazole (7-NI), a specific inhibitor of the nNOS enzyme. However, contrasting results obtained with the toxin, the effect of Ca 2+ influx via N-type Ca 2+ channels on PnPP-19-mediated erection was irrelevant ( Silva et al, 2021 ). Likewise, previous result observed with the toxin PnTx2-6 ( Nunes et al, 2010 ), activation of muscarinic receptors in the endothelium is not involved in this peptide’s action.…”

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 97%

“…Likewise, previous result observed with the toxin PnTx2-6 ( Nunes et al, 2010 ), activation of muscarinic receptors in the endothelium is not involved in this peptide’s action. In both cases there was non-participation of acetylcholine (Ach) in the mechanism of action of these compounds, implying that although PnTx2-6 and PnPP-19 exhibit many differences, they also share similar characteristics ( Silva et al, 2021 ). Table 1 summarizes a comparison between the PnTx2-6 and PnPP-19 peptide.…”

Section: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

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: The Toxin Pntx2-6 Versus Pnpp-19 In Erect...mentioning

confidence: 74%