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Design of sodium channel ligands with defined selectivity – a case study in scorpion alpha‐toxins
Author(s) -
Kuldyushev Nikita A.,
Berkut Antonina A.,
Peigneur Steve,
Tytgat Jan,
Grishin Eugene V.,
Vassilevski Alexander A.
Publication year - 2017
Publication title -
febs letters
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.593
H-Index - 257
eISSN - 1873-3468
pISSN - 0014-5793
DOI - 10.1002/1873-3468.12839
Subject(s) - selectivity , sodium channel , scorpion toxin , scorpion , toxin , chemistry , gene isoform , sodium , stereochemistry , biochemistry , gene , venom , organic chemistry , catalysis
Scorpion α‐toxins are polypeptides that inhibit voltage‐gated sodium channel inactivation. They are divided into mammal, insect and α‐like toxins based on their relative activity toward different phyla. Several factors are currently known to influence the selectivity, which are not just particular amino acid residues but also general physical, chemical, and topological properties of toxin structural modules. The objective of this study was to change the selectivity profile of a chosen broadly active α‐like toxin, BeM9 from Mesobuthus eupeus , toward mammal‐selective. Based on the available information on what determines scorpion α‐toxin selectivity, we designed and produced msBeM9, a BeM9 derivative, which was verified to be exclusively active toward mammalian sodium channels and, most importantly, toward the Na v 1.2 isoform expressed in the brain.