title: Pharmacological profiling of Orthochirus scrobiculosus toxin 1 analogs with a trimmed N-terminal domain.
abstract: OSK1, a toxin from the venom of the Asian scorpion Orthochirus scrobiculosus, is a 38-residue peptide cross-linked by three disulfide bridges. A structural analog of OSK1, [Lys(16),Asp(20)]-OSK1, was found previously to be one of the most potent blockers of the voltage-gated K(+) channel Kv1.3 hitherto characterized. Here, we demonstrate that progressive trimming of the N-terminal domain of [Lys(16),Asp(20)]-OSK1 results in marked changes in its pharmacological profile, in terms of both K(+) channel affinity and selectivity. Whereas the affinity to Kv1.1 and Kv1.3 did not change significantly, the affinity to Kv1.2 and K(Ca)3.1 was drastically reduced with the truncations. It is surprising that a striking gain in potency was observed for Kv3.2. In contrast, a truncation of the C-terminal domain, expected to partially disrupt the toxin beta-sheet structure, resulted in a significant decrease or a complete loss of activity on all channel types tested. These data highlight the value of structure-function studies on the extended N-terminal domain of [Lys(16),Asp(20)]-OSK1 to identify new analogs with unique pharmacological properties.
authors.affiliation: Laboratoire Cellpep S.A., Marseille, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Mouhat
authors.forename: Georgeta
authors.initials: G
authors.lastname: Teodorescu
authors.forename: Daniel
authors.initials: D
authors.lastname: Homerick
authors.forename: Violeta
authors.initials: V
authors.lastname: Visan
authors.forename: Heike
authors.initials: H
authors.lastname: Wulff
authors.forename: Yingliang
authors.initials: Y
authors.lastname: Wu
authors.forename: Stephan
authors.initials: S
authors.lastname: Grissmer
authors.forename: Hervé
authors.initials: H
authors.lastname: Darbon
authors.forename: Michel
authors.initials: M
authors.lastname: De Waard
authors.forename: Jean-Marc
authors.initials: JM
authors.lastname: Sabatier
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D002460:Cell Line; D006801:Humans; D051379:Mice; D008969:Molecular Sequence Data; D019906:Nuclear Magnetic Resonance, Biomolecular; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D012604:Scorpion Venoms / Q000737:chemistry*; D017386:Sequence Homology, Amino Acid; D014118:Toxins, Biological / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D010455:Peptides; D012604:Scorpion Venoms; D014118:Toxins, Biological