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Discovery and design of novel inhibitors of botulinus neurotoxin A: targeted ‘hinge’ peptide libraries
Author(s) -
Hayden J.,
Pires J.,
Roy S.,
Hamilton M.,
Moore G. J.
Publication year - 2003
Publication title -
journal of applied toxicology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.784
H-Index - 87
eISSN - 1099-1263
pISSN - 0260-437X
DOI - 10.1002/jat.870
Subject(s) - chemistry , linker , peptide , stereochemistry , amino acid , docking (animal) , biochemistry , tripeptide , protease , enzyme , medicine , nursing , computer science , operating system
Intoxication by the zinc protease botulinus neurotoxin A (BoNT‐A) results from cleavage of a single Q–R bond in the neuronal protein SNAP‐25, which disables the docking mechanism required for neurotransmitter release. In the present study, potential inhibitors of BoNT‐A were assessed from their effects on the BoNT‐A cleavage of a synthetic 17‐mer peptide (SNAP‐25, residues 187–203) spanning the Q–R cleavage site. Compounds that inhibited BoNT‐A included thiols (zinc chelators) such as dithiothreitol, dimercaptopropanesulfonic acid, mercaptosuccinic acid and captopril. In addition, compounds containing multiple acidic functions, such as the SNARE motif V2 (ELDDRADALQ), the tripeptide Glu‐Glu‐Glu and the steroid glycoside glycyrrhizic acid, were effective inhibitors. ‘Hinge’ peptide mini‐libraries (PMLs) having the structure acetyl‐X 1 ‐X 2 ‐linker‐X 3 ‐X 4 ‐NH 2 or X 1 ‐X 2 ‐linker‐X 3 , where X 1 –X 4 were mixtures of selected amino acids and the flexible linker was 4‐aminobutyric acid, also provided effective inhibition. Targeted PMLs containing the acidic amino acids Asp and Glu, the scissile‐bond amino acids Gln and Arg and the zinc chelators His and Cys produced pronounced inhibition of BoNT‐A. Deconvolution of these libraries will provide novel ligands with improved inhibitory potency as leads in the design of peptide mimetics to treat BoNT poisoning. Copyright ? 2003 Crown in the right of Canada. Published by John Wiley and Sons, Ltd.