Scientists have engineered a new antidote for death cap poisoning

The death cap is the world’s most poisonous mushroom, responsible for over 90% of mushroom-related deaths worldwide.
Loukia Papadopoulos
Mushrooms in the wild.jpg
Mushrooms in the wild.

Robert Winkler/iStock 

Scientists have developed a new antidote now approved by the U.S. Food and Drug Administration called indocyanine green that reduces the toxicity of α-amanitin, a toxin produced by the world’s most poisonous mushroom: the death cap. Trials thus far have been successful in human cell lines and mice. 

This is according to a press release from Springer Nature published on Tuesday.

The results of the research thus far indicate that this new substance could present a potential antidote treatment for death cap poisoning in humans, responsible for over 90 percent of mushroom-related deaths worldwide. 

40,000 illnesses and 788 deaths

Mushroom poisoning is the main cause of mortality in food poisoning incidents worldwide,” said a press release for the new announcement. “ In China alone, almost 40,000 illnesses and 788 deaths were reported between 2010–2020. α-amanitin is the main toxin produced by the death cap mushroom and causes high rates of irreparable liver or kidney damage and mortality following consumption. Despite its lethal effects, the exact molecular mechanisms of α-amanitin’s toxicity remain unclear, and no specific antidote is currently available.”

The new antidote was developed by Qiaoping Wang and colleagues, who used genome-wide CRISPR screening to identify molecular targets for α-amanitin. Through this process, they discovered that the protein STT3B, a key component of the N-glycan biosynthesis pathway involved in protein folding and trafficking in a large number of biological recognition events, is required for α-amanitin toxicity. 

They then applied a virtual drug screening to pinpoint indocyanine green as an inhibitor of STT3B that may prevent liver toxicity. Perhaps more importantly, indocyanine green was also found to increase the probability of survival of human cell lines and mice exposed to α-amanitin.

More research needed

The next stages of the work will now focus on further research to understand the exact mechanisms indocyanine green uses to inhibit α-amanitin and assess its safety for use in humans. However, it should be noted that the new method of combining genome-wide CRISPR screening with virtual drug screening could be used to help quickly identify new antidotes for other medically relevant human poisons.

The study was published in a Nature Communications paper.

Study abstract:

The “death cap,” Amanita phalloides, is the world’s most poisonous mushroom, responsible for 90% of mushroom-related fatalities. The most fatal component of the death cap is α-amanitin. Despite its lethal effect, the exact mechanisms of how α-amanitin poisons humans remain unclear, leading to no specific antidote available for treatment. Here we show that STT3B is required for α-amanitin toxicity and its inhibitor, indocyanine green (ICG), can be used as a specific antidote. By combining a genome-wide CRISPR screen with an in silico drug screening and in vivo functional validation, we discover that N-glycan biosynthesis pathway and its key component, STT3B, play a crucial role in α-amanitin toxicity and that ICG is a STT3B inhibitor. Furthermore, we demonstrate that ICG is effective in blocking the toxic effect of α-amanitin in cells, liver organoids, and male mice, resulting in an overall increase in animal survival. Together, by combining a genome-wide CRISPR screen for α-amanitin toxicity with an in silico drug screen and functional validation in vivo, our study highlights ICG as a STT3B inhibitor against the mushroom toxin.