Engineers transform the antique toxic tomb mushroom into anti-cancer drugs

Researchers led by Penn have transformed a fatal fungus into a powerful compound against cancer. After isolating a new class of Aspergillus Flavus molecules, a toxic fungus of cultures linked to death in the excavations of the old tombs, the researchers modified the chemicals and tested them against leukemic cells. The result? A promising compound of cancer killers that compete with drugs approved by the FDA and opens up new borders in the discovery of more fungal drugs.

“Mushrooms have given us penicillin,” explains Sherry Gao, associate professor of compact presidential elections in chemical and biomolecular (CBE) and bio-engineering (BE) and principal author of a new article in Chemical biology of nature on the results. “These results show that many more drugs derived from natural products remain to be found.”

From curse to healing

Aspergillus Flavus, named after his yellow spores, has long been a microbial villain. After archaeologists opened the tomb of King Tutankhamun in the 1920s, a series of premature deaths among the excavation team fueled the rumors of the curse of a pharaoh. Decades later, doctors theorized that fungal spores, dormant for millennia, could have played a role.

In the 1970s, a dozen scientists entered the tomb of Casimir IV in Poland. In a few weeks, 10 of them died. Subsequent surveys have revealed that the tomb contained A. Flavus, whose toxins can cause pulmonary infections, especially in people with compromise immune systems.

Now, this same fungus is the improbable source of a new promising cancer therapy.

Rare fungal find

The therapy in question is a class of peptides, or ripps modified by ribosomal and post-transduction, pronounced like the “RIP” in a piece of fabric. The name refers to how the compound is produced – by ribosome, a tiny cellular structure that manufactures proteins – and the fact that it is later modified, in this case, to improve its properties of cancer killers.

“The purification of these chemicals is difficult,” explains Qiuyue Nie, postdoctoral scholarship holder of CBE and the first author of the newspaper. While thousands of Ripp have been identified in bacteria, only one handle was found in the mushrooms. Partly, this is due to the fact that the former researchers have poorly identified fungal ripps as non -ribosomal peptides and did not understand how the fungi created the molecules.

“The synthesis of these compounds is complicated,” adds Nie. “But that is also what gives them this remarkable bioactivity.”

Chemicals hunting

To find more fungal RIPPS, the researchers first scanned a dozen Aspergillus strains, which the suggested previous research could contain more chemicals.

By comparing the chemicals produced by these strains with known RIPP construction blocks, the researchers identified A. Flavus as a promising candidate for a more in -depth study.

Genetic analysis highlighted a particular protein in A. Flavus as a source of fungal ripps. When the researchers overturned the genes that create this protein, the chemical markers indicating the presence of RIPP have also disappeared.

This new approach – combining metabolic and genetic information – has not only identified the source of fungal Ripps at A. Flavus, but could be used to find more fungal ripps in the future.

A new powerful drug

After having purified four different Ripp, the researchers discovered that the molecules shared a unique structure of nested rings. The researchers appointed these molecules, which were never described previously, after the fungus in which they were found: asperigimycins.

Even without modification, when mixed with human cancer cells, aspérigimycins have demonstrated a medical potential: two of the four variants have had powerful effects against leukemic cells.

Another variant, to which the researchers added a lipid or greasy molecule, which is also in the royal jelly which nourishes the developing bees, carried out as well as the cytarabine and the Daunorubicin, two drugs approved by the FDA which have been used for decades to treat leukemia.

Cracking the cell entry code

To understand why lipids have improved the power of aspérigimycins, researchers have selectively activated and disabled genes in leukemic cells. A gene, SLC46A3, proved to be critical to allow aspérigimycins to enter leukemia cells in sufficient number.

This gene helps materials to leave lysosomes, the tiny bags that collect foreign materials entering human cells. “This gene acts like a bridge,” said Nie. “It does not only help asperigimycins to get into cells, it can also allow other” cyclical peptides “to do the same.”

Like aspérigimycins, these chemicals have medicinal properties – in fact that two dozen cyclical peptides have received clinical approval since 2000 to treat such varied diseases such as cancer and lupus, but many of them need modifications to enter the cells in sufficient quantities.

“Knowing that lipids can affect the way this gene transports chemicals in cells gives us another drug development tool,” said NIE.

Disturb the cell division

Thanks to a new experiment, the researchers have found that Asperigimycins probably disrupt the cellular division process. “The cancer cells are divided uncontrollable,” explains Gao. “These compounds block the formation of microtubules, which are essential for cell division.”

In particular, the compounds have had little or no effect on cancer cells in breast, liver or lung – or a range of bacteria and fungi – suggesting that the disturbing effects of asperigimycins are specific to certain types of cells, a critical characteristic for any future medication.

Future directions

In addition to demonstrating the medical potential of asperigimycins, the researchers have identified similar bunches of genes in other fungi, which suggests that more fungal ripps remain to be discovered. “Even if only a few have been found, almost all have strong bioactivity,” said Nie. “This is an unexplored region with enormous potential.”

The next step is to test asperigimycins in animal models, with the hope of one day spending human clinical trials. “Nature gave us this incredible pharmacy,” explains Gao. “It is up to us to discover its secrets. As an engineers, we are delighted to continue to explore, learn from nature and use this knowledge to design better solutions.”