Inhibitory Activity of Calcium and Sodium Ion Channels of Neurotoxic Protoplaythoa variabilis V-Shape Helical Peptide Analogs and Their Neuroprotective Effect In Vitro

<b>Background/Objectives:</b> One of the neurotoxic components from the sea trumpet polyps, <i>Protopalythoa variabilis</i> (Cnidaria, Anthozoa), is a 26-residue, V-shape helical peptide (PpVα). Its synthetic versions, i.e., the linear, the single-disulfide-bonded analog, and the chimeric peptide with a 6-residue stretch of the N-terminal native homologous peptide covalently linked to the linear sequence, were investigated for their activity on ion channels responsible for cellular excitability and synaptic transmission. <b>Methods:</b> Molecular docking analyses and dynamic simulations focused on the ability of PpVα peptides to bind ion channels selectively through interaction with critical residues at their binding sites. <b>Results:</b> Electrophysiological studies using the patch clamp technique with sympathetic bovine chromaffin cells from the adrenal medulla confirmed that PpVα analogs can block both sodium and calcium currents, which are responsible for initiating and propagating action potentials, respectively, and for neurotransmitter release. Additionally, the peptides displayed neuroprotective effects, attenuating cellular damage induced by veratridine, which interferes with sodium channel activity, and by oligomycin and rotenone (O/R), which affect mitochondrial function. <b>Conclusions:</b> The block of calcium and sodium channels and the neuroprotective effects against oxidative stress make the PpVα peptide scaffold an attractive template for developing agents that has significant clinical potential in several areas, such as the treatment of neurological diseases (epilepsy, multiple sclerosis, and neurodegenerative diseases), neuroprotection in acute events (stroke and traumatic brain or spinal cord injuries), the management of neuropathic pain, the prevention of ischemic damage, and psychiatric disorders (anxiety and bipolar disorder).