title: A branched peptide mimotope of the nicotinic receptor binding site is a potent synthetic antidote against the snake neurotoxin alpha-bungarotoxin.
abstract: We previously produced synthetic peptides mimicking the snake neurotoxin binding site of the nicotinic receptor. These peptide mimotopes bind the snake neurotoxin alpha-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 alpha-bungarotoxin in solution and inhibits its binding to the receptor with a K(A) and an IC(50) 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.
authors.affiliation: Department of Molecular Biology, Laboratory of Biotechnology, University of Siena, Italy. braccil@unisi.it
authors.forename: Luisa
authors.initials: L
authors.lastname: Bracci
authors.forename: Luisa
authors.initials: L
authors.lastname: Lozzi
authors.forename: Alessandro
authors.initials: A
authors.lastname: Pini
authors.forename: Barbara
authors.initials: B
authors.lastname: Lelli
authors.forename: Chiara
authors.initials: C
authors.lastname: Falciani
authors.forename: Neri
authors.initials: N
authors.lastname: Niccolai
authors.forename: Andrea
authors.initials: A
authors.lastname: Bernini
authors.forename: Adriano
authors.initials: A
authors.lastname: Spreafico
authors.forename: Patrizia
authors.initials: P
authors.lastname: Soldani
authors.forename: Paolo
authors.initials: P
authors.lastname: Neri
mesh_terms: D000818:Animals; D000931:Antidotes / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D001665:Binding Sites; D001667:Binding, Competitive; D002038:Bungarotoxins / Q000037:antagonists & inhibitors* / Q000633:toxicity; D000939:Epitopes / Q000008:administration & dosage / Q000737:chemistry / Q000378:metabolism / Q000494:pharmacology; D007279:Injections, Subcutaneous; D007928:Lethal Dose 50; D008024:Ligands; D051379:Mice; D018716:Molecular Mimicry; D010446:Peptide Fragments / Q000008:administration & dosage / Q000138:chemical synthesis* / Q000378:metabolism / Q000494:pharmacology*; D011978:Receptors, Nicotinic / Q000378:metabolism*
chemical_list: D000931:Antidotes; D002038:Bungarotoxins; D000939:Epitopes; D008024:Ligands; D010446:Peptide Fragments; D011978:Receptors, Nicotinic