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

Abstract

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.

Chemical Synthesis and Insecticidal Activity Research Based on α-Conotoxins

“…For decades, the research on the activity of marine peptides has focused on analgesia, anti-cancer, anti-epilepsy, and other significant diseases, such as conotoxin MVIIA, which has been approved by the FDA as advanced cancer analgesics [ 33 , 34 , 35 ]. However, most of the peptide toxins secreted by marine organisms are used to prey on arthropods, such as worms and shrimp.…”

Analgesic Peptides: From Natural Diversity to Rational Design

“…The most toxic components derived from this venom are neurotoxins PnTx2-6 (δ-CNTX-Pn2a) and PnTx2-5. These molecules contain 48 amino acid residues (Table 4) [55,71,72]. PnTx2-6 modulates voltage-gated Na + channels and stimulates the production of nitric oxide (NO).…”

“…However, PnTx2-6 induces nociception but is highly toxic; therefore, its therapeutic use is not possible. To overcome these limitations, the synthetic 19 amino acid peptide PnPP-19 was developed (Ac-GERRQYFWIAWYKLANSKKa) [72]. This molecule does not act on the Na v channels but shows great potential as a therapeutic drug without significant toxicity.…”

“…The PnPP-19 can act on the activation of DOR, MOR, or CB1 cannabinoid receptors. Moreover, the antinociception induced by this peptide appears to involve the inhibition of neprilysin, a neutral endopeptidase that prevents the destruction of endogenous opioids [72].…”

Editorial: Venom peptides: A rich combinatorial library for drug development, volume II

“…Editorial on the Research Topic Venom peptides: A rich combinatorial library for drug development, volume II Peptide toxins are the main components of venoms and have been selected during the evolution process of venomous animals to specifically interfere with the vital physiological systems of their victims, a crucial step for prey capture or defence against predators (von Reumont et al, 2022). These small-reticulated and highly resistant peptides interact with high affinity and selectivity with their molecular targets and have been exploited as valuable pharmacological tools to study these receptors and ion channels or for therapeutic purposes (Cardoso, 2020;da Silva et al, 2022;Gilles and Servent, 2014;Herzig et al, 2020). About ten venom-derived drugs already reach the market to treat type-2 diabetes, chronic pain, hypertension or acute coronary syndrome and several dozen are in clinical trials and preclinical investigations (Fischer and Riedl, 2022).…”