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

February 17, 2022 Leave a comment
PnPP-19 peptide has a primary sequence design based on molecular modeling studies of PnTx2-6 toxin. It comprises the amino acid residues that are potentially significant for the pharmacological action of PnTx2-6. Ex vivo and in vivo experiments in normotensive, hypertensive, or diabetic murine models have shown a significant improvement in penile erection after administration of PnPP-19. Given the potential use of PnPP-19 in pharmaceutical formulations to treat erectile dysfunction and the lack of information concerning its mode of action, the present work investigates its activities on the nitrergic system. PnPP-19 induced a significant increase in nitric oxide (NO) and cGMP levels in corpus cavernosum (cc).
These effects were inhibited by L-NAME, a non-selective inhibitor of nitric oxide synthase (NOS); were partially inhibited by 7- Nitroindazole, a selective inhibitor of neuronal NOS (nNOS); and were abolished by L-NIL, a selective inhibitor of inducible NOS (iNOS). This potentiating effect was not affected by atropine. PnPP-19 also led to changes in mRNA levels, protein expression and phosphorylation at specific sites of NOS, in cc. Assays using cavernous tissue from knockout mice to endothelial NOS (eNOS), nNOS or iNOS showed that PnPP-19 potentiates relaxation only in eNOS-knockout mice, which suggests an essential role for nNOS. Surprisingly, iNOS enhanced the potentiation of erectile function evoked by PnPP-19. Our results demonstrate that this new synthetic peptide potentiates erectile function via nitric oxide activation and reinforce its role as a new pharmacological tool for the treatment of erectile dysfunction.

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

Purpose: Evaluation of PnPP-19 safety and efficacy in reducing the intraocular pressure (IOP) of animals with healthy (normotensive) and ocular hypertensive eyes. PnPP-19 is a synthetic peptide designed from Phoneutria nigriventer spider toxin PnTx2-6.
Methods: Toxicity tests used chicken chorioallantoic membranes. Electroretinograms (ERGs) were recorded before and after administration of different doses of PnPP-19 on the eyes of Wistar rats. Histological sections of corneas and retinas were prepared. The efficacy of PnPP-19 in reducing IOP was evaluated for normotensive and ocular hypertensive animals using a tonometer. Ocular hypertension was induced in the right eye through injection of hyaluronic acid (HA) into the anterior chamber. ERG was recorded before and after glaucoma induction. The eyes were enucleated, and the corneas and retinas were histologically evaluated.
Results: PnPP-19 showed no toxicity, being safe for ocular application. A single topical instillation of one eye drop of the peptide solution was able to reduce IOP, both in healthy and ocular hypertensive rats, for 24 hours, without eliciting any apparent toxicity. PnPP-19 is a nitric oxide inducer and the results suggest that it may improve the conventional outflow of aqueous humor (AH), preventing the progression of optic nerve degeneration.
Conclusions: PnPP-19 has great potential to emerge as a promising drug for the treatment of ocular hypertension.
Translational relevance: We regard our findings as exciting progress in translational glaucoma research, combining drug discovery, natural product research, and pharmacology, which may contribute to the establishment of new therapies for the treatment of this disease.

PnPP-19 Peptide Restores Erectile Function in Hypertensive and Diabetic Animals Through Intravenous and Topical Administration.

With the aim of overcoming the high toxicity of PnTx2-6 (or δ-CNTX-Pn2a), a toxin from the venom of the armed spider (Phoneutria nigriventer), the 19-aminoacid peptide, PnPP-19 (P nigriventer potentiator peptide), was synthesized based on molecular modeling studies of PnTx2-6. PnPP-19 improved the erectile function of normotensive rats and mice, without eliciting side effects, and no signs of toxicity were observed.
In addition, PnPP-19 was able to potentiate the effect of sildenafil.To evaluate the efficacy of PnPP-19 in hypertensive and diabetic mouse/rat models in restoring erectile function, after topical administration; verify the biodistribution of PnPP-19 administration (topical and intravenous), permeation, and cyclic guanosine monophosphate (cGMP)/nitric oxide via implication.
METHODS

Corpus cavernosum relaxation was evaluated using cavernous strips from male spontaneous hypertensive rats (SHR) and from streptozotocin (STZ)-diabetic mice contracted with phenylephrine and submitted to electrical field stimulation before and after incubation with PnPP-19 (10-8 mol/L, 10 minutes) or vehicle. This procedure was also used to determine cGMP/nitric oxide levels, at 8 Hz and to check the effect of PnPP-19 with sildenafil citrate. Biodistribution assays were performed using iodine 123-radiolabeled PnPP-19. In vivo erectile function was evaluated using intracavernosal pressure/main arterial pressure ratio in STZ-diabetic rats after PnPP-19 topical administration.

MAIN OUTCOME MEASURES

PnPP-19 may become a new drug able to fill the gap in the pharmacologic treatment of erectile dysfunction, especially for hypertensive and diabetic individuals RESULTS: PnPP-19 potentiated corpus cavernosum relaxation, in both control and SHR rats. SHR-cavernosal tissue treated with PnPP-19 (1-32 Hz) reached the same relaxation levels as control Wistar rats (16 and 32 Hz). PnPP-19 treatment improved cavernosal tissue relaxation in STZ-diabetic mice and rats. PnPP-19 enhanced cGMP levels in STZ-diabetic mice corpus cavernosum strips. After topical or intravenous administration in rats, 123I-PnPP-19 was mainly recruited to the penis. When topically administered (400 μg/rat), PnPP-19 restores erectile function in STZ-diabetic rats, also improving it in healthy rats by increasing the intracavernosal pressure/main arterial pressure ratio. PnPP-19 exhibited an additive effect when co-administered with sildenafil, showing a novel mode of action regardless of phosphodiesterase type 5 inhibition.PnPP-19 seems to be an indicated drug to be tested to treat ED in diabetic and hypertensive patients.PnPP-19, although active by topical application and showing safety to human beings (not shown), has low permeability, about 10% of the applied dose.Our results showed that PnPP-19 may emerge as a potent new drug that can be topically administered, becoming a promising alternative for erectile dysfunction treatment. Nunes da Silva C, Pedrosa Nunes K, De Marco Almeida F, et al. PnPP-19 Peptide Restores Erectile Function In Hypertensive And Diabetic Animals Through Intravenous And Topical Administration. J Sex Med 2019;16:365-374.

PNPP
C6959-1000 ApexBio 1g 40 EUR

PNPP
C6959-500 ApexBio 500mg 28 EUR

PNPP
HY-15928 MedChemExpress 1g 142.8 EUR

PNPP
T16554-10mg TargetMol Chemicals 10mg Ask for price

PNPP
T16554-1g TargetMol Chemicals 1g Ask for price

PNPP
T16554-1mg TargetMol Chemicals 1mg Ask for price

PNPP
T16554-50mg TargetMol Chemicals 50mg Ask for price

PNPP
T16554-5mg TargetMol Chemicals 5mg Ask for price

pNPP
MBS238301-100mL MyBiosource 100mL 235 EUR

pNPP
MBS238301-5x100mL MyBiosource 5x100mL 875 EUR

pNPP
MBS238302-500mL MyBiosource 500mL 680 EUR

pNPP
MBS238302-5x500mL MyBiosource 5x500mL 2875 EUR

PNPP
MBS3845744-500mg MyBiosource 500mg 135 EUR

PNPP
MBS3845744-5x500mg MyBiosource 5x500mg 600 EUR

PNPP
MBS5755394-1g MyBiosource 1g 150 EUR

PNPP
MBS5755394-500mg MyBiosource 500mg 145 EUR

PNPP
MBS5755394-5x1g MyBiosource 5x1g 525 EUR

pNPP Reagent
GWB-Q00238 GenWay Biotech 100 ml Ask for price

pNPP Reagent
GWB-Q00239 GenWay Biotech 500 ml Ask for price

pNPP Substrate
X156-11ML Arbor Assays 11ML 218 EUR

PNPP Substrate
F008-22 Cygnus Technologies 22 ml 216 EUR

pNPP Substrate
4400A Kementec Solutions 1 L 424.6 EUR

pNPP Substrate
4400H Kementec Solutions 100 ML 77 EUR

pNPP Substrate
4400L Kementec Solutions 500 ML 287.1 EUR

pNPP for ELISA
42R-1005 Fitzgerald 500 ml 300 EUR

PNPP sodium salt
GX9577 Glentham Life Sciences 5g 138.82 EUR

PNPP sodium salt
GX9577-25 Glentham Life Sciences 25 151.6 EUR

PNPP sodium salt
GX9577-5 Glentham Life Sciences 5 46.6 EUR

pNPP ONE Substrate
4401A Kementec Solutions 1 L 424.6 EUR

pNPP ONE Substrate
4401H Kementec Solutions 100 ML 77 EUR

The Peptide PnPP-19, a Spider Toxin Derivative, Activates μ-Opioid Receptors and Modulates Calcium Channels.

The synthetic peptide PnPP-19 comprehends 19 amino acid residues and it represents part of the primary structure of the toxin δ-CNTX-Pn1c (PnTx2-6), isolated from the venom of the spider Phoneutria nigriventer. Behavioural tests suggest that PnPP-19 induces antinociception by activation of CB1, μ and δ opioid receptors. Since the peripheral and central antinociception induced by PnPP-19 involves opioid activation, the aim of this work was to identify whether this synthetic peptide could directly activate opioid receptors and investigate the subtype selectivity for μ-, δ- and/or κ-opioid receptors.
Furthermore, we also studied the modulation of calcium influx driven by PnPP-19 in dorsal root ganglion neurons, and analyzed whether this modulation was opioid-mediated. PnPP-19 selectively activates μ-opioid receptors inducing indirectly inhibition of calcium channels and hereby impairing calcium influx in dorsal root ganglion (DRG) neurons. Interestingly, notwithstanding the activation of opioid receptors, PnPP-19 does not induce β-arrestin2 recruitment. PnPP-19 is the first spider toxin derivative that, among opioid receptors, selectively activates μ-opioid receptors. The lack of β-arrestin2 recruitment highlights its potential for the design of new improved opioid agonists.

Leave a Reply

Your email address will not be published.