Yin Kathleen, Deuis Jennifer R, Dekan Zoltan, Jin Ai-Hua, Alewood Paul F, King Glenn F, Herzig Volker, Vetter Irina
Centre for Health Informatics, Australian Institute of Health Innovation, Macquarie University, North Ryde, NSW 2109, Australia.
Institute for Molecular Bioscience, The University of Queensland, St. Lucia, QLD 4072, Australia.
Biomedicines. 2020 Feb 19;8(2):37. doi: 10.3390/biomedicines8020037.
Spider venom is a novel source of disulfide-rich peptides with potent and selective activity at voltage-gated sodium channels (Na). Here, we describe the discovery of μ-theraphotoxin-Pme1a and μ/-theraphotoxin-Pme2a, two novel peptides from the venom of the Gooty Ornamental tarantula that modulate Na channels. Pme1a is a 35 residue peptide that inhibits Na1.7 peak current (IC 334 ± 114 nM) and shifts the voltage dependence of activation to more depolarised membrane potentials (V activation: Δ = +11.6 mV). Pme2a is a 33 residue peptide that delays fast inactivation and inhibits Na1.7 peak current (EC > 10 μM). Synthesis of a [+22K]Pme2a analogue increased potency at Na1.7 (IC 5.6 ± 1.1 μM) and removed the effect of the native peptide on fast inactivation, indicating that a lysine at position 22 (Pme2a numbering) is important for inhibitory activity. Results from this study may be used to guide the rational design of spider venom-derived peptides with improved potency and selectivity at Na channels in the future.
蜘蛛毒液是富含二硫键的肽的一种新来源，这些肽对电压门控钠通道（Na）具有强大且选择性的活性。在此，我们描述了μ-瑟拉毒素-Pme1a和μ/-瑟拉毒素-Pme2a的发现，这两种来自古氏华丽雨林蜘蛛毒液的新型肽可调节钠通道。Pme1a是一种由35个氨基酸残基组成的肽，它可抑制Na1.7的峰值电流（IC 334 ± 114 nM），并将激活的电压依赖性转移到更去极化的膜电位（V激活：Δ = +11.6 mV）。Pme2a是一种由33个氨基酸残基组成的肽，它可延迟快速失活并抑制Na1.7的峰值电流（EC > 10 μM）。[+22K]Pme2a类似物的合成提高了对Na1.7的效力（IC 5.6 ± 1.1 μM），并消除了天然肽对快速失活的影响，这表明第22位（Pme2a编号）的赖氨酸对抑制活性很重要。本研究的结果可能用于指导未来合理设计在钠通道上具有更高效力和选择性的蜘蛛毒液衍生肽。
