Copper Complex Halts Botulinum Neurotoxin Poisoning

A new study describes how a readily available metal salt could provide a new therapy for Botulinum Neurotoxin type A (BoNT/A), the most common and deadly cause of human botulism.

Researchers at the Scripps Research Institute (TSRI; La Jolla, CA, USA), Boston University (MA, USA), and other institutions conducted a study that screened various triazole compounds against the BoNT/A light chain (LC) protease, a proteolytic enzyme that disrupts neuronal signaling to muscles. They found to their surprise that it was metal salts, and not the triazole compounds that showed marked inhibitory activity, and that copper cations in particular displayed noncompetitive inhibition of the LC, with mercury cations 10-fold more potent.

They then examined ligand-copper complexes in a cell-based model, and found that they too prevented BoNT/A cleavage of the endogenous protein substrate (SNAP-25) even at low μM concentrations. The researchers suggest that a bio-reductive mechanism caused an intracellular release of copper, which directly inhibited the BoNT/A protease. Further in-vivo experiments in rodents showed that copper (II) dithiocarbamate and bis(thiosemicarbazone) complexes could be used to treat the harmful effects of BoNT/A intoxication. The study was published on May 5, 2017, in JACS.

“Currently, botulism sufferers receive an anti-toxin medicine that can inactivate the toxin circulating in their system, thereby preventing further poisoning. However, the anti-toxin cannot reverse preexisting paralysis because the toxin acts inside cells,” said lead author Professor Kim Janda, PhD, of the TSRI department of chemistry. “Consequently, disease recovery can be slow, and paralysis may take weeks or months to wear off. This new therapy can readily enter cells where it can attack the etiological agent, a protease, which is responsible for paralysis seen from the neurotoxin.”

BoNT-A is probably best known as Botox, an injectable toxin commonly used to treat various movement disorders, such as focal dystonias, and in cosmetic treatments by paralyzing smooth muscles that cause wrinkles. It is also one of the most potent toxins on earth, and is classified as a potential bioterrorism threat, together with as Anthrax, Plague, Ebola, and other Category A priority pathogens.

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