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Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors.
FASEB J. 2019 03; 33(3):3693-3703.FJ

Abstract

A 13 aa residue voltage-gated sodium (NaV) 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 NaV 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 NaV channel inhibitor was active on NaV1.2. Through the generation of 3 series of peptide mutants, we investigated the role of key residues and cyclization and their influence on NaV inhibition and subtype selectivity. Cyclic PnCS1, a 10 residue peptide cyclized via a disulfide bond, exhibited increased inhibitory activity toward therapeutically relevant NaV channel subtypes, including NaV1.7 and NaV1.9, while displaying remarkable serum stability. These peptides represent the first and the smallest cyclic peptide NaV 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.

Authors+Show Affiliations

Toxicology and Pharmacology, Katholieke Universiteit (KU) Leuven, Campus Gasthuisberg, Leuven, Belgium. Department de Bioquímica e Imunologia, Laboratório de Venenos e Toxinas Animais, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo-Horizonte, Brazil.Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.Department of Biophysics, Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University Jena, Germany.Department of Biophysics, Center for Molecular Biomedicine, Jena University Hospital, Friedrich Schiller University Jena, Germany.Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.Laboratory of Medicinal Chemistry, Rega Institute for Medical Research, Katholieke Universiteit (KU) Leuven, Leuven, Belgium.Department de Bioquímica e Imunologia, Laboratório de Venenos e Toxinas Animais, Instituto de Ciências Biológicas, Universidade Federal de Minas Gerais, Belo-Horizonte, Brazil. Programa de Pós-Graduação em Ciências da Saúde, Biomedicina e Medicina, Instituto de Ensino e Pesquisa da Santa Casa de Belo Horizonte, Grupo Santa Casa de Belo Horizonte, Belo Horizonte, Brazil.Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.Institute for Molecular Bioscience, The University of Queensland, Brisbane, Queensland, Australia.Toxicology and Pharmacology, Katholieke Universiteit (KU) Leuven, Campus Gasthuisberg, Leuven, Belgium.

Pub Type(s)

Journal Article
Research Support, Non-U.S. Gov't

Language

eng

PubMed ID

30509130

Citation

Peigneur, Steve, et al. "Where Cone Snails and Spiders Meet: Design of Small Cyclic Sodium-channel Inhibitors." FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, vol. 33, no. 3, 2019, pp. 3693-3703.
Peigneur S, Cheneval O, Maiti M, et al. Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors. FASEB J. 2019;33(3):3693-3703.
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. (2019). Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors. FASEB Journal : Official Publication of the Federation of American Societies for Experimental Biology, 33(3), 3693-3703. https://doi.org/10.1096/fj.201801909R
Peigneur S, et al. Where Cone Snails and Spiders Meet: Design of Small Cyclic Sodium-channel Inhibitors. FASEB J. 2019;33(3):3693-3703. PubMed PMID: 30509130.
* Article titles in AMA citation format should be in sentence-case
TY - JOUR T1 - Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors. AU - Peigneur,Steve, AU - Cheneval,Olivier, AU - Maiti,Mohitosh, AU - Leipold,Enrico, AU - Heinemann,Stefan H, AU - Lescrinier,Eveline, AU - Herdewijn,Piet, AU - De Lima,Maria Elena, AU - Craik,David J, AU - Schroeder,Christina I, AU - Tytgat,Jan, Y1 - 2018/12/03/ PY - 2018/12/5/pubmed PY - 2019/11/13/medline PY - 2018/12/5/entrez KW - peptide cyclization KW - peptide toxin KW - toxin-based therapeutics KW - voltage-gated sodium channel SP - 3693 EP - 3703 JF - FASEB journal : official publication of the Federation of American Societies for Experimental Biology JO - FASEB J. VL - 33 IS - 3 N2 - A 13 aa residue voltage-gated sodium (NaV) 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 NaV 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 NaV channel inhibitor was active on NaV1.2. Through the generation of 3 series of peptide mutants, we investigated the role of key residues and cyclization and their influence on NaV inhibition and subtype selectivity. Cyclic PnCS1, a 10 residue peptide cyclized via a disulfide bond, exhibited increased inhibitory activity toward therapeutically relevant NaV channel subtypes, including NaV1.7 and NaV1.9, while displaying remarkable serum stability. These peptides represent the first and the smallest cyclic peptide NaV 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. SN - 1530-6860 UR - https://www.unboundmedicine.com/medline/citation/30509130/Where_cone_snails_and_spiders_meet:_design_of_small_cyclic_sodium_channel_inhibitors_ L2 - http://www.fasebj.org/doi/full/10.1096/fj.201801909R?url_ver=Z39.88-2003&rfr_id=ori:rid:crossref.org&rfr_dat=cr_pub=pubmed DB - PRIME DP - Unbound Medicine ER -