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Potential Antidote Discovered for Centuries-Old Toxic Mushroom
The allure of food for free has led many out into the woods to forage for wild mushrooms. Although appealing, guidance and training is critical for the sport as the abundance of toxic toadstools makes it especially dangerous for novices.
Among the many varieties of poisonous mushrooms, perhaps the most infamous is Amanita phalloides, better known as the death cap mushroom. This spore-bearer causes most yearly mushroom poisonings and 90% of fatalities thereof.
Tales of its reputation are such that it is supposedly the cause of death for Roman Emperor Claudius and Holy Roman Emperor Charles VI. It is speculated that as little as half of one death cap can be fatal; the days after ingestion being particularly unpleasant: punctuated by seizures, vomiting, and diarrhoea.
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Although notoriously deadly, their exact method of poisoning has been fairly enigmatic. Scientists already knew that the lethal toxin was the chemical ?-amanitin but did not fully understand its mechanism of action. As a result, no specific antidote had yet been found.
That is until research published in Nature Communications claimed to have discovered the biochemical pathway that is the root of the mushroom’s deadliness. The paper says that the enzyme STT3B is required for ?-amanitin toxicity which can be blocked by the chemical indocyanine green (ICG), a possible antidote for A. phalloides poisoning.
Nature reported Helge Bode, a professor and chemist at the Max Planck Institute for Terrestrial Microbiology said of the news: “That’s fantastic, ?-Amanitin really is one of the most dangerous compounds that we have in nature.”
A team of scientists from Sun Yat-sen University in Guangzhou, China conducted this research using a genome-wide CRISPR loss-of-function screen to identify which genes and pathways were involved with ?-amanitin’s toxicity.
This led them to identify the N-Glycan biosynthesis pathway, which requires the STT3B enzyme, as a biological function that is essential for ?-amanitin to be toxic: block this pathway, and you block the toxicity. The next step was to find an STT3B inhibitor. Although was no known FDA approved inhibitor of this enzyme, the team set to work on using in silico screening to find one.
They screened a total of 3201 FDA approved compounds from the libraries ZINC and Drugbank which was narrowed down to 34 candidates for in vitro cellular validation. In vitro testing led to ICG and posaconazole being selected as potential antidotes.
This led the team to use liver organoids to further validate the candidate with successful results. This prompted further in vivo modelling, this time to test the efficacy of ICG on ?-amanitin poisoned mice. Their impressive final results from the mouse models showed that they could reduce the lethality of the poison from 90% to around 50%.
ICG is already approved for use in humans by the FDA and EMA as a dye used in imaging, so clinical trials for the compound as an antidote is straightforward in theory. However, although the molecule is proven safe, a clinical trial would rest on sourcing patients that had just ingested death cap. Therefore, timing would be paramount for in human testing.
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