Premium
Where cone snails and spiders meet: design of small cyclic sodium‐channel inhibitors
Author(s) -
Peigneur Steve,
Cheneval Olivier,
Maiti Mohitosh,
Leipold Enrico,
Heinemann Stefan H.,
Lescrinier Eveline,
Herdewijn Piet,
De Lima Maria Elena,
Craik David J.,
Schroeder Christina I.,
Tytgat Jan
Publication year - 2019
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fj.201801909r
Subject(s) - peptide , chemistry , sodium channel , cyclic peptide , pharmacophore , stereochemistry , residue (chemistry) , toxin , nav1 , scorpion toxin , biophysics , biochemistry , sodium , biology , organic chemistry
A 13 aa residue voltage‐gated sodium (Na v ) channel inhibitor peptide, Pn, containing 2 disulfide bridges was designed by using a chimeric approach. This approach was based on a common pharmacophore deduced from sequence and secondary structural homology of 2 Na V inhibitors: Conus kinoshitai toxin IIIA, a 14 residue cone snail peptide with 3 disulfide bonds, and Phoneutria nigriventer toxin 1, a 78 residue spider toxin with 7 disulfide bonds. As with the parent peptides, this novel Na V channel inhibitor was active on Na V 1.2. Through the generation of 3 series of peptide mutants, we investigated the role of key residues and cyclization and their influence on Na V inhibition and subtype selectivity. Cyclic PnCS1, a 10 residue peptide cyclized via a disulfide bond, exhibited increased inhibitory activity toward therapeutically relevant Na V channel subtypes, including Na V 1.7 and Na V 1.9, while displaying remarkable serum stability. These peptides represent the first and the smallest cyclic peptide Na V modulators to date and are promising templates for the development of toxin‐based therapeutic agents.—Peigneur, S., Cheneval, O., Maiti, M., Leipold, E., Heinemann, S. H., Lescrinier, E., Herdewijn, P., De Lima, M. E., Craik, D. J., Schroeder, C. I., Tytgat, J. Where cone snails and spiders meet: design of small cyclic sodium‐channel inhibitors. FASEB J. 33, 3693–3703 (2019). www.fasebj.org