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Where cone snails and spiders meet: design of small cyclic sodium-channel inhibitors
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 J. 33(3): 3693-3703. https://hdl.handle.net/10.1096/fj.201801909R
In: The FASEB Journal. Federation of American Societies for Experimental Biology: Bethesda, Md.. ISSN 0892-6638; e-ISSN 1530-6860
Peer reviewed article  

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Author keywords
    voltage-gated sodium channel; peptide cyclization; toxin-basedtherapeutics; peptide toxin

Auteurs  Top 
  • 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.

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.

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