Use of synthetic analogs for a study on the structure-activity relationship of apamin.
[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.
D000595:Amino Acid Sequence; D000818:Animals; D001030:Apamin / Q000031:analogs & derivatives / Q000138:chemical synthesis* / Q000633:toxicity; D001514:Bee Venoms / Q000138:chemical synthesis*; D007928:Lethal Dose 50; D008297:Male; D008722:Methods; D051379:Mice; D009498:Neurotoxins; D013329:Structure-Activity Relationship
D001514:Bee Venoms; D009498:Neurotoxins; D001030:Apamin