Structurally Diverse μ‐Conotoxin PIIIA Isomers Block Sodium Channel Na_V1.4

Abstract

The one and only fold? Three chemically synthesized μ‐conotoxin PIIIA isomers (see picture), which contain different disulfide connectivity, block the skeletal muscle voltage‐gated sodium channel NaV1.4 with similar, yet distinguishable potency. Hence, bioactivity of this μ‐conotoxin is not strictly coupled to its native fold. Future development of conotoxin‐derived analgesics may benefit from such a widened structural repertoire.

Design of Bioactive Peptides from Naturally Occurring μ-Conotoxin Structures

“…Despite the lack of an ␣-helix, the Midi peptide blocks Na v s at nanomolar concentrations. This is in accord with recent studies of an isomer of PIIIA that also had a flexible conformation but remained active on Na v 1.4 (44). Apparently, an ␣-helix is not strictly essential to acquire a fully active peptide.…”

“…Recently, it was proven by molecular dynamic simulations for PIIIA that differences in binding affinity on Na v 1.4 can be due to a slightly different location of binding in the pore region. One of its structural isomers was simulated to bind to a region located deeper in the pore, correlating to a higher binding affinity on Na v 1.4 (44). Consequently, small differences in binding affinities reveal that our -conotoxin derivatives bind at slightly different regions, although all located in the pore and therefore leading to block of Na ϩ conduction.…”

Synthetic Cystine-Knot Miniproteins – Valuable Scaffolds for Polypeptide Engineering

“…Engineered agatoxin AgTx, a knottin from spider venom, was shown to bind with high affinity to a tumor-associated receptor target in a glioblastoma xenograft model [100]. Interestingly, although it is generally accepted that the native fold of the voltage-gating toxins carries the ICK disulfide connectivities as a prerequisite for bioactivity, disulfide engineering of μ-conotoxin PIIIA leading to unusual cystine combinations I-V, II-VI, III-IV and I-II, III-IV, V-VI resulted in miniproteins that were able to block sodium channels [103].…”

Molecular interaction of δ-conopeptide EVIA with voltage-gated Na+ channels

“…For example, µ-conotoxins interact with voltage-gated Na + (Na V ) channels by occluding the pore via binding in the extracellularly accessible channel vestibule. [11] This relatively simple interaction mechanism and the perspective to develop µ-conotoxins as drugs to suppress neuronal signaling and therefore to be applied as analgesics has fueled research in this direction. [12] Conotoxins of the O-superfamily also contain three disulfide bridges, but they are much more diverse.…”