European journal of pharmacology · 2026
The new vrdg183 toxin from the Colombian spider Pamphobeteus verdolaga inhibits L-type Ca2+ currents through an allosteric mechanism.
СтатьяНазвание и аннотация: Перевод в очереди
Обработка статьи · этапы, ошибки и управление
Загрузка состояния…
Ошибки и ограничения
История · было → стало
Состояние обновляется каждые 5 секунд, пока блок открыт. Процент показывается только там, где известен объём работы. Пауза останавливает продолжение этапа; текущий запрос к источнику может завершиться.
Gómez-Restrepo Alejandro, Rojas-Palomino Jessica, Salinas-Restrepo Cristian, Segura César, Saurith-Coronell Oscar A, Márquez-Brazón Edgar A, Giraldo Marco A, Calderón Juan C
Аннотация
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.
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.