Addition of K22 Converts Spider Venom Peptide Pme2a from an Activator to an Inhibitor of NaV1.7

• Published in: Biomedicines Vol. 8; no. 2; p. 37
• Main Authors: Yin, Kathleen, Deuis, Jennifer R., Dekan, Zoltan, Jin, Ai-Hua, Alewood, Paul F., King, Glenn F., Herzig, Volker, Vetter, Irina
• Format: Journal Article
• Language: English
• Published: MDPI 19.02.2020; MDPI AG
• Subjects: nav1.7; nav1.8; peptide; sodium channel; spider; venom
• ISSN: 2227-9059; 2227-9059
• DOI: 10.3390/biomedicines8020037

Spider venom is a novel source of disulfide-rich peptides with potent and selective activity at voltage-gated sodium channels (NaV). Here, we describe the discovery of μ-theraphotoxin-Pme1a and μ/δ-theraphotoxin-Pme2a, two novel peptides from the venom of the Gooty Ornamental tarantula Poecilotheria metallica that modulate NaV channels. Pme1a is a 35 residue peptide that inhibits NaV1.7 peak current (IC50 334 ± 114 nM) and shifts the voltage dependence of activation to more depolarised membrane potentials (V1/2 activation: Δ = +11.6 mV). Pme2a is a 33 residue peptide that delays fast inactivation and inhibits NaV1.7 peak current (EC50 > 10 μM). Synthesis of a [+22K]Pme2a analogue increased potency at NaV1.7 (IC50 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 NaV channels in the future.