Global & Disaster Medicine

Compounds containing copper and other metal salts were tested in mice, which like humans are vulnerable to the toxin’s blockage of nerve signals to muscles. They penetrated to the site of the neurotoxin’s action, extending the lives of the mice that were given lethal doses.

San Diego Union Tribune


Metal Ions Effectively Ablate the Action of Botulinum Neurotoxin A

Paul T. Bremer, Sabine Pellett, James Patrick Carolan, William H. Tepp, Lisa M Eubanks, Karen N Allen, Eric A. Johnson,  and Kim D Janda
J. Am. Chem. Soc.,
DOI: 10.1021/jacs.7b01084
Publication Date (Web): May 5, 2017
Copyright © 2017 American Chemical Society

Abstract:  “Botulinum neurotoxin serotype A (BoNT/A) causes a debilitating and potentially fatal illness known as botulism. The toxin is also a known bioterror threat, yet no pharmacological antagonists to counteract its effects has reached clinical approval. Existing strategies to negate BoNT/A intoxication have looked to antibodies, peptides or organic small molecules as potential therapeutics. In this work, a departure from the traditional drug discovery mindset was pursued, in which the enzyme’s susceptibility to metal ions was exploited. A screen of a series of metal salts showed marked inhibitory activity of group 11 and 12 metals against the BoNT/A light chain (LC) protease. Enzyme kinetics revealed that copper (I) and (II) cations displayed noncompetitive inhibition of the LC (Ki ≈ 1 µM), while mercury (II) cations were 10-fold more potent. Crystallographic and mutagenesis studies elucidated a key binding interaction between Cys165 on BoNT/A LC and the inhibitory metals. As potential copper prodrugs, ligand-copper complexes were examined in a cell-based model and were found to prevent BoNT/A cleavage of the endogenous protein substrate, SNAP-25, even at low µM concentrations of complexes. Further investigation of the complexes suggested a bioreductive mechanism causing intracellular release of copper, which directly inhibited the BoNT/A protease. In vivo experiments demonstrated that dithiocarbamate and bis(thiosemicarbazone) copper (II) complexes could delay BoNT/A-mediated lethality in a rodent model, indicating their potential for treating the harmful effects of BoNT/A intoxication. Our studies illustrate that metals can be therapeutically viable enzyme inhibitors; moreover, enzymes that share homology with BoNT LCs may be similarly targeted with metals.”

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