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Pharmacological Profiling of Orthochirus scrobiculosus Toxin 1 Analogs with a Trimmed N-Terminal Domain

Laboratoire Cellpep S.A., Marseille, France; Centre National de la Recherche Scientifique Formation de Recherche en Evolution 2738, Marseille, France (S.M., J.-M.S.); Universität Ulm, Ulm, Germany (G.T., V.V., S.G.); Department of Medical Pharmacology and Toxicology, University of California, Davis, Davis, California (D.H., H.W.); College of Life Sciences, Wuhan University, Wuhan, China (Y.W.); AFMB, Centre National de la Recherche Scientifique UPR 9039, Marseille, France (H.D.); Institut National de la Santé et de la Recherche Médicale U607, Département Réponse Dynamique et Cellulaire, Grenoble, France; CEA, Grenoble, France; and Université Joseph Fourier, Grenoble, France (M.D.W.)

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, [Lys¹⁶,Asp²⁰]-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 [Lys¹⁶,Asp²⁰]-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_Ca3.1 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 -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 [Lys¹⁶,Asp²⁰]-OSK1 to identify new analogs with unique pharmacological properties.

Address correspondence to: Dr. Jean-Marc Sabatier, Centre National de la Recherche Scientifique Formation de Recherche en Evolution 2738, Boulevard Pierre Dramard, 13916 Marseille Cedex 20, France. E-mail: sabatier.jm{at}jean-roche.univ-mrs.fr

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