Study of enhancing analgesic potential of μ-conotoxins from the computational and pharmacological insights

μ-Conotoxins target voltage-gated sodium channels, with KIIIA, CnIIIC, and SxIIIC showing notable inhibition of Na_V1.7, which is strongly implicated in pain signaling. This study focuses on three such peptides-KIIIA, CnIIIC, and SxIIIC-and investigates their potential as analgesic according to the elucidation of their selectivity mechanism against different channel subtypes. Using computational simulations and pharmacological assays, we identified the critical role of the basic residues at the C-terminal of μ-conotoxin in binding to Na_V channels. Two engineered mutants, R10E^KIIIA and R20W^CnIIIC, demonstrated significantly enhanced analgesic activity in vivo compared to their wild-type toxins. These findings highlight the potential of rational μ-conotoxin engineering for developing effective and safer pain therapeutics.