Synthesis, 3-D structure, and pharmacology of a reticulated chimeric peptide derived from maurotoxin and Tsk scorpion toxins.

Abstract Maurotoxin (MTX) is a 34-mer scorpion toxin cross-linked by four disulfide bridges that acts on both Ca 2+ -activated (SK) and voltage-gated (Kv) K + channels. A 38-mer chimera of MTX, Tsk-MTX, has been synthesized by the solid-phase method. It encompasses residues from 1 to 6 of Tsk at N-terminal, and residues from 3 to 34 of MTX at C-terminal. As established by enzyme cleavage, Tsk-MTX displays half-cystine pairings of the type C1-C5, C2-C6, C3-C7 and C4-C8 which, contrary to MTX, correspond to a disulfide bridge pattern common to known scorpion toxins. The 3-D structure of Tsk-MTX, solved by 1 H NMR, demonstrates that it adopts the α/β scaffold of scorpion toxins. In vivo, Tsk-MTX is lethal by intracerebroventricular injection in mice (LD 50 value of 0.2 μg/mouse). In vitro, Tsk-MTX is as potent as MTX, or Tsk, to interact with apamin-sensitive SK channels of rat brain synaptosomes (IC 50 value of 2.5 nM). It also blocks voltage-gated K + channels expressed in Xenopus oocytes, but is inactive on rat Kv1.3 contrary to MTX.