Structure-function and rational design of a spider toxin Ssp1a at human voltage-gated sodium channel subtypes
Dongol, Yashad, Wilson, David T., Daly, Norelle L., Cardoso, Fernanda C., and Lewis, Richard J. (2023) Structure-function and rational design of a spider toxin Ssp1a at human voltage-gated sodium channel subtypes. Frontiers in Pharmacology, 14. 1277143.
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Abstract
The structure-function and optimization studies of NaV-inhibiting spider toxins have focused on developing selective inhibitors for peripheral pain-sensing NaV1.7. With several NaV subtypes emerging as potential therapeutic targets, structure-function analysis of NaV-inhibiting spider toxins at such subtypes is warranted. Using the recently discovered spider toxin Ssp1a, this study extends the structure-function relationships of NaV-inhibiting spider toxins beyond NaV1.7 to include the epilepsy target NaV1.2 and the pain target NaV1.3. 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 NaV subtypes, especially at NaV1.3 (∼10-fold), while N14D-P27R-rSsp1a enhanced NaV1.2/1.7 selectivity over NaV1.3. This study highlights the challenge of developing subtype-selective spider toxin inhibitors across multiple NaV 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 NaV1.2, NaV1.3 and/or NaV1.7 as research tools and therapeutic leads.
| Item ID: | 81469 |
|---|---|
| Item Type: | Article (Research - C1) |
| ISSN: | 1663-9812 |
| Keywords: | ICK toxins, rational design, spider toxin, Ssp1a, structure-function, voltage-gated sodium channels |
| Copyright Information: | © 2023 Dongol, Wilson, Daly, Cardoso and Lewis. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms. |
| Date Deposited: | 05 Mar 2024 00:46 |
| FoR Codes: | 32 BIOMEDICAL AND CLINICAL SCIENCES > 3205 Medical biochemistry and metabolomics > 320599 Medical biochemistry and metabolomics not elsewhere classified @ 100% |
| SEO Codes: | 28 EXPANDING KNOWLEDGE > 2801 Expanding knowledge > 280103 Expanding knowledge in the biomedical and clinical sciences @ 100% |
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