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

Abstract

Introduction 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. Aim 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. Clinical Implications PnPP-19 seems to be an indicated drug to be tested to treat ED in diabetic and hypertensive patients. Strength & Limitations PnPP-19, although active by topical application and showing safety to human beings (not shown), has low permeability, about 10% of the applied dose. Conclusion 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.

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

“…This finding is therapeutically relevant given the clinical routine, highlighting that, despite reducing IOP by around 30% after 24 hours of a single instillation, PnPP-19 did not change MAP as previously described. 20,40 A commercial prostaglandin-analog antiglaucoma agent (Bimatoprost) was used to compare its effects with those of PnPP-19. IOP lowering remained for 24 hours after the treatment with a single topical instillation of PnPP-19.…”

“…This finding is therapeutically relevant given the clinical routine, highlighting that, despite reducing IOP by around 30% after 24 hours of a single instillation, PnPP-19 did not change MAP as previously described. 20 , 40 …”

“…Then, the eggshells were opened and the inner membranes were carefully removed. PnPP-19 (40,80,160, and 320 μg) were applied to CAM and the membranes were observed during 300 seconds. Saline (0.9% NaCl) was used as a negative control and sodium hydroxide (NaOH 0.1M) as a positive control (N = 10).…”

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

“…These results can be explained due to the unrelated mechanisms of action of each drug. Both PnPP-19 and sildenafil act on the NO/cGMP pathway, PnPP-19 increases NO production and consequently cGMP levels within the smooth muscle cells in the CC, while sildenafil prevents decreasing cGMP levels ( Silva et al, 2019 ). In addition, PnPP-19 was able to reverse the ED phenotype in spontaneously hypertensive rats and diabetic mice and rats.…”

“…In addition, PnPP-19 was able to reverse the ED phenotype in spontaneously hypertensive rats and diabetic mice and rats. In a model of type 1 STZ-induced diabetic mice, relaxation following PnPP-19 treatment in CC strips was 83% higher compared to untreated animals ( Silva et al, 2019 ).…”