PnPP-19 potentiates erection in vivo and ex vivo via the nitric oxide/cyclic guanosine monophosphate pathway. It does not affect sodium channels or rat hearts and shows no toxicity and low immunogenicity. These findings make it a promising candidate as a novel drug in the therapy of erectile dysfunction.
Venom variability in specimens of Tityus serrulatus scorpion was assessed by matrix-assisted laser desorption/ionization time-of-flight mass spectrometry (MALDI-TOFMS) analyses. An expanded time lag venom extraction protocol was carried out using ten scorpions to study individual variations that might occur due to different rates in protein expression and/or processing. The first extraction of venom was made from the animals after 20 days of starvation, which allowed the venom gland to be filled up. The second extraction event was carried out 24 hours after the first one. The third was 8 days after the first extraction. By means of MALDI-TOF analyses, important variations were observed in venoms of a single specimen extracted at different times, especially in latter extraction events. These variations are most probably related to dynamics in cell gland production. Since T. serrulatus is a parthenogenetic species, sexual variations are naturally excluded and we did not expect intra-specific variations, which was confirmed. Knowledge of individual venom variability is extremely important to avoid misunderstandings in the use of venom proteomic analysis as a taxonomic tool.
Antimicrobial peptides (AMPs) have been found in all organism taxa and may play an essential
role as a host defense system. AMPs are organized in various conformations, such as linear
peptides, disulfide bond-linked peptides, backbone-linked peptides and circular peptides. AMPs apparently
act primarily on the plasma membrane, although an increasing number of works have shown that
they may also target various intracellular sites. Spider venoms are rich sources of biomolecules that
show several activities, including modulation or blockage of ion channels, anti-insect, anti-cancer,
antihypertensive and antimicrobial activities, among others. In spider venoms from the Lycosidae
family there are many linear AMPs with a wide range of activities against several microorganisms.
Due to these singular activities, some Lycosidae AMPs have been modified to improve or decrease
desirable or undesirable effects, respectively. Such modifications, especially with the aim of increasing
their antibiotic activity, have led to the filing of many patent applications. This review explores the
abundance of Lycosidae venom AMPs and some of their derivatives, and their use as new drug models.
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.
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