A Branched Peptide Mimotope of the Nicotinic Receptor Binding Site Is a Potent Synthetic Antidote against the Snake Neurotoxin α-Bungarotoxin

We previously produced synthetic peptides mimicking the snake neurotoxin binding site of the nicotinic receptor. These peptide mimotopes bind the snake neurotoxin α-bungarotoxin with higher affinity than peptides reproducing native receptor sequences and inhibit toxin binding to nicotinic receptors...

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Bibliographic Details
Published in:Biochemistry (Easton) 2002-08, Vol.41 (32), p.10194-10199
Main Authors: Bracci, Luisa, Lozzi, Luisa, Pini, Alessandro, Lelli, Barbara, Falciani, Chiara, Niccolai, Neri, Bernini, Andrea, Spreafico, Adriano, Soldani, Patrizia, Neri, Paolo
Format: Article
Language:English
Subjects:
Animals
Antidotes - administration & dosage
Antidotes - chemical synthesis
Antidotes - metabolism
Antidotes - pharmacology
Binding Sites
Binding, Competitive
Bungarotoxins - antagonists & inhibitors
Bungarotoxins - toxicity
Epitopes - administration & dosage
Epitopes - chemistry
Epitopes - metabolism
Epitopes - pharmacology
Injections, Subcutaneous
Lethal Dose 50
Ligands
Mice
Molecular Mimicry
Peptide Fragments - administration & dosage
Peptide Fragments - chemical synthesis
Peptide Fragments - metabolism
Peptide Fragments - pharmacology
Receptors, Nicotinic - metabolism
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Summary:We previously produced synthetic peptides mimicking the snake neurotoxin binding site of the nicotinic receptor. These peptide mimotopes bind the snake neurotoxin α-bungarotoxin with higher affinity than peptides reproducing native receptor sequences and inhibit toxin binding to nicotinic receptors in vitro; yet their efficiency in vivo is low. Here we synthesized one of the peptide mimotopes in a tetrabranched MAP form. The MAP peptide binds α-bungarotoxin in solution and inhibits its binding to the receptor with a K A and an IC50 similar to the monomeric peptide. Nonetheless, it is at least 100 times more active in vivo. The MAP completely neutralizes toxin lethality when injected in mice at a dose compatible with its use as a synthetic antidote in humans. The in vivo efficacy of the tetrameric peptide cannot be ascribed to a kinetic and thermodynamic effect and is probably related to different pharmacokinetic behavior of the tetrameric molecule, with respect to the monomer. Our findings bring new perspectives to the therapeutic use of multimeric peptides.
ISSN:0006-2960
1520-4995
DOI:10.1021/bi0256025