The study of toxins and venom-derived peptides has revolutionized our understanding of ion channels, uncovering new pathways for therapeutic development. Several venom-inspired ion channel targeting peptides have progressed to clinical development. For instance:

Ziconotide, a synthetic ω-conotoxin peptide from cone snails, is used to treat pain by inhibiting the CaV2.2 channel.

XEP-018, a NaV1.4 blocker inspired by cone snail μ-conotoxins, has found applications in cosmetics.

Dalazatide, a Kv1.3 inhibitor derived from sea anemone toxins, has been tested for rheumatoid arthritis.

SOR-C13, a TRPV6 inhibitor, has shown promise in early clinical trials and has received orphan drug designation for certain cancers.

The advent of computational tools and the growing availability of ion channel crystal structures have made it increasingly feasible to design novel venom-inspired peptides with enhanced selectivity. High-throughput automated patch clamp (APC) platforms are accelerating this process in industrial drug discovery and academic research alike.

Nanion’s automated patch clamp systems, such as the SyncroPatch 384 and Patchliner, have been instrumental in many recent discoveries in toxin research:

+ Researchers identified TMEM233, a transmembrane protein critical for the activity of Excelsatoxin A (ExTxA), a pain-inducing peptide from the Australian stinging tree. This finding revealed TMEM233 as a novel NaV1.7-interacting protein, offering new therapeutic targets for pain management.

+ Ant venom peptides have been shown to modulate voltage-gated sodium channels (NaV), altering their activation thresholds and inactivation properties—mechanisms that explain the painful effects of ant stings.

Additionally, these platforms have facilitated:

+ Insights into marine brevetoxins’ modulation of various NaV channels, including NaV1.2, NaV1.4, NaV1.5, and NaV1.7.

+ Development of photoactivatable peptide toxins, like modified ProTx-II and HwTx-IV, for precise control of voltage-gated ion channels and cell excitability.

+ Characterization of novel toxins like conotoxin Mu8.1 from the fish-hunting cone snail, a potent CaV2.3 inhibitor.

+ Creation of functional fluorescent-tagged α-bungarotoxin for studying nicotinic acetylcholine receptors.

Marine Toxins: Saxitoxin, tetrodotoxin, and brevetoxins provide insights into sodium channel modulation with applications in seafood safety and environmental monitoring.

Spider Venom Peptides: Phlotoxin-1 (PhlTx1), ProTx-II, PcTx1, Hi1a and Hc3a target sodium or ASIC channels for therapeutic applications in pain management and neuroprotection.

Scorpion Venom Peptides: BmK AGP-SYPU1 and Iberiotoxin (IbTX) target NaV and Kv channels for immune and vascular therapeutic uses. Alpha-KTx 15.1 selectively inhibits Kv3.1 channels, offering insights into neuronal excitability. Urotoxin (α-KTx 6) inhibits Kv1.2 channels, contributing to vascular research. A pore-forming Smp24 exhibits antimicrobial activity.

Sea Anemone Toxins: ShK peptides are under development as Kv1.3 inhibitors for autoimmune disease management. Actinoporins, such as equinatoxins and mytiporins, are pore-forming toxins that disrupt membrane integrity and influence calcium signaling.

Bee Venom Peptides: Xylopin, a peptide from Xylocopa appendiculata circumvolans, exhibiting broad-spectrum antimicrobial activity and pore-forming mechanisms.

Wasp Venom Peptides: Eumenitin-R, Eumenitin-F: antimicrobial peptides. Polybia-MPII shows potent antimicrobial and antifungal activity, disrupting microbial membranes. EMP-ER and EMP-EF: Mast cell-degranulating peptides from solitary wasp venom.

Ant Venom Peptides: Ta3a, Pc1a, Rm4a and Mri1a pain-inducing toxins target sodium channels in vertebrates, contributing to studies on nociception.

Pore-Forming Fungal and Bacterial Toxins: Pore-forming toxins (PFTs) like candidalysin, pneumolysin, aerolysin, listeriolysin O, thermostable direct hemolysin as well as diphtheria toxin and anthrax toxin, are studied for their roles in fungal and bacterial pathogenesis. For such studies of PFTs, both patch clamp and bilayer recording systems, like the Orbit mini or the Orbit 16, are often employed.

Synthetic and Engineered Toxins: Photoactivatable toxins (like modified ProTx-II and HwTx-IV) and fluorescent-tagged peptides (like α-Bungarotoxin) are innovative tools for ion channel studies.

With ongoing advancements in high-throughput screening technologies and computational design, venom-inspired peptides continue to unlock new opportunities in ion channel drug discovery. These biologics promise improved safety profiles and enhanced therapeutic efficacy, paving the way for innovative treatments across a range of conditions.

The studies highlight the diverse therapeutic potential of toxins and their derived peptides:

Pain Management – NaV1.7 inhibitors like ProTx-II are promising candidates for treating chronic and neuropathic pain.

Autoimmune Diseases – Kv1.3 inhibitors, such as ShK peptides, are being developed for diseases like multiple sclerosis and rheumatoid arthritis.

Neuroprotection – ASIC1a inhibitors like PcTx1 and Hi1a show potential in reducing acidotoxicity during ischemic stroke.

Cardiovascular Diseases – Kv11.1 (hERG) modulators like APETx1 are explored for preventing arrhythmias, while KCa1.1 modulators like IbTX are studied for hypertension.

Cancer – Scorpion venom peptides like AGAP have shown potential anti-tumor activity.

Infectious Diseases – Toxins such as candidalysin have been studied for their roles in fungal pathogenesis, with efforts to develop neutralizing strategies.