The new vrdg183 toxin from the Colombian spider Pamphobeteus verdolaga inhibits L-type Ca2+ currents through an allosteric mechanism

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The new vrdg183 toxin from the Colombian spider Pamphobeteus verdolaga inhibits L-type Ca2+ currents through an allosteric mechanism

Abstract

Background

Spider venoms are enriched in toxins that modulate mammalian voltage-gated ion channels (VGIC) with pharmacological potential. However, the inventory of toxins of American spiders with effects on voltage-gated Ca2+ channels has lagged the number of toxins interacting with other channels. Here, we aimed at identifying new Ca2+ channel-modulating toxins of the Colombian spider Pamphobeteus verdolaga.

Methods

The sequences of five novel short, positively charged, disulfide-bridged peptides, and one more short, non-bridged control peptide, were selected from the transcriptomic database of the venom gland of P. verdolaga. Peptides were synthesized and screened at 1 μM for their effects on L-type Ca2+ currents (ICaL) in mouse cardiomyocytes using patch-clamp. IK were also evaluated to gain information about the selectivity of the peptides. 3D modeling, docking and molecular dynamics simulations were likewise performed.

Results

vrdg183 (19 amino acid residues, four cysteines, charge +7, 2.33 kDa), followed by vrdg69 and vrdg177, inhibited over 60% of ICaL. vrdg172 and vrdg164 showed a moderate effect of less than 40%. vrdg183 had a half-maximal inhibitory concentration for ICaL of 858.28 nM and was the only toxin lacking effect on IK. vrdg183, consisting of two antiparallel β-strands, was successfully docked to the extracellular L6IV loop at the outer pore region of the human cardiac Cav1.2 with a binding energy of -9.5 kJ/mol. Conclusion: This is the first report of toxins of P. verdolaga with effects on VGIC. vrdg183 highlights as a very low molecular weight, moderately potent ICaL inhibitor through an allosteric mechanism, without effect on IK.

Gómez-Restrepo, A., Rojas-Palomino, J., Salinas-Restrepo, C., Segura, C., Saurith-Coronell, O. A., Márquez-Brazón, E. A., Giraldo, M. A., & Calderón, J. C. (2026). The new vrdg183 toxin from the Colombian spider Pamphobeteus verdolaga inhibits L-type Ca2+ currents through an allosteric mechanism. European Journal of Pharmacology, 178524. https://doi.org/10.1016/j.ejphar.2026.178524