Journal Article

Structure-function and rational design of a spider toxin Ssp1a at human voltage-gated sodium channel subtypes

Lewis, Richard J., Cardoso, Fernanda C., Daly, Norelle L., Dongol, Yashad, Wilson, David T.

2023

Overview

The structure-function and optimization studies of Na V -inhibiting spider toxins have focused on developing selective inhibitors for peripheral pain-sensing Na V 1.7. With several Na V subtypes emerging as potential therapeutic targets, structure-function analysis of Na V -inhibiting spider toxins at such subtypes is warranted. Using the recently discovered spider toxin Ssp1a, this study extends the structure-function relationships of Na V -inhibiting spider toxins beyond Na V 1.7 to include the epilepsy target Na V 1.2 and the pain target Na V 1.3. Based on these results and docking studies, we designed analogues for improved potency and/or subtype-selectivity, with S7R-E18K-rSsp1a and N14D-P27R-rSsp1a identified as promising leads. S7R-E18K-rSsp1a increased the rSsp1a potency at these three Na V subtypes, especially at Na V 1.3 (∼10-fold), while N14D-P27R-rSsp1a enhanced Na V 1.2/1.7 selectivity over Na V 1.3. This study highlights the challenge of developing subtype-selective spider toxin inhibitors across multiple Na V subtypes that might offer a more effective therapeutic approach. The findings of this study provide a basis for further rational design of Ssp1a and related NaSpTx1 homologs targeting Na V 1.2, Na V 1.3 and/or Na V 1.7 as research tools and therapeutic leads.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Channel gating / Design / Epilepsy / ICK toxins / NMR / Nuclear magnetic resonance / Pain / Peptides / Pharmacology / rational design / Sodium channels (voltage-gated) / spider toxin / Ssp1a / structure-function / Structure-function relationships / Therapeutic targets / Toxins / voltage-gated sodium channels