Use of Synthetic Analogs for a Study on the Structure‐Activity Relationship of Apamin

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Abstract
[Lys13, Lys14]Apamin, [Lys13]apamin and [Lys14]apamin, three structural analogs of the bee venom neurotoxin, have been obtained by solid-phase peptide synthesis while an attempt to obtain [Cit13]apamin failed, probably at the step of reoxidation of cysteines. After the chemical purity of these three derivatives had been assessed, further chemical modifications led to three new peptides: [Ac-Cys1, Lys(Ac)4, Lys(Ac)13]apamin, [Ac-Cys1, Lys(Ac)4, Lys(Ac)14]apamin and [Har4, Har13, Har14]apamin. These six analogs have been tested for their neurotoxicity, i.e. determination of LD50 for mouse by subcutaneous injection. A lethal potency is observed only when the region 13–14 of the sequence contains a double positive charge. One arginyl residue is necessary for a high biological activity, while its location in position 13 or 14 is of minor importance. When homoarginine (Har) replaces arginyl residues the neurotoxicity is lowered.

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