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Design of bioactive peptides from naturally occurring µ-conotoxin structures
Stevens, M.; Peigneur, S.; Dyubankova, N.; Lescrinier, E.; Herdewijn, P.; Tytgat, J. (2012). Design of bioactive peptides from naturally occurring µ-conotoxin structures. J. Biol. Chem. 287(37): 31382-31392. dx.doi.org/10.1074/jbc.M112.375733
In: Journal of Biological Chemistry. American Society for Biochemistry and Molecular Biology: Baltimore, etc.. ISSN 0021-9258; e-ISSN 1083-351X
Peer reviewed article  

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  • Stevens, M.
  • Peigneur, S.
  • Dyubankova, N.
  • Lescrinier, E.
  • Herdewijn, P.
  • Tytgat, J.

Abstract
    To date, cone snail toxins (“conotoxins”) are of great interest in the pursuit of novel subtype-selective modulators of voltage-gated sodium channels (Navs). Navs participate in a wide range of electrophysiological processes. Consequently, their malfunctioning has been associated with numerous diseases. The development of subtype-selective modulators of Navs remains highly important in the treatment of such disorders. In current research, a series of novel, synthetic, and bioactive compounds were designed based on two naturally occurring µ-conotoxins that target Navs. The initial designed peptide contains solely 13 amino acids and was therefore named “Mini peptide.” It was derived from the µ-conotoxins KIIIA and BuIIIC. Based on this Mini peptide, 10 analogues were subsequently developed, comprising 12–16 amino acids with two disulfide bridges. Following appropriate folding and mass verification, blocking effects on Navs were investigated. The most promising compound established an IC50 of 34.1 ± 0.01 nm (R2-Midi on Nav1.2). An NMR structure of one of our most promising compounds was determined. Surprisingly, this structure does not reveal an a-helix. We prove that it is possible to design small peptides based on known pharmacophores of µ-conotoxins without losing their potency and selectivity. These data can provide crucial material for further development of conotoxin-based therapeutics.

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