Optimizing Nav1.7-Targeted Analgesics: Revealing Off-Target Effects of Spider Venom-Derived Peptide Toxins and Engineering Strategies for Improvement.

ABSTRACT: The inhibition of Nav1.7 is a promising strategy for the development of analgesic treatments. Spider venom-derived peptide toxins are recognized as significant sources of Nav1.7 inhibitors. However, their development has been impeded by limited selectivity. In this study, eight peptide toxins from three distinct spider venom Nav channel families demonstrated robust inhibition of hNav1.7, rKv4.2, and rKv4.3 (rKv4.2/4.3) currents, exhibiting a similar mode of action. The analysis of structure and function relationship revealed a significant overlap in the pharmacophore responsible for inhibiting hNav1.7 and rKv4.2 by HNTX-III, although Lys25 seems to play a more pivotal role in the inhibition of rKv4.2/4.3. Pharmacophore-guided rational design is employed for the development of an mGpTx1 ana

SUBMITTER: Luo S 

PROVIDER: S-EPMC11558128 | biostudies-literature | 2024 Nov

REPOSITORIES: biostudies-literature