A fatal fungus linked to death in archaeologists searched the old graves has been transformed into a new compound against cancer. A team from the University of Pennsylvania has modified some of the chemicals of the toxic cultures of cultures Aspergillus flavus, Aka the mushroom of the curse “pharaohs”, and has created a new compound that kills leukemia cells. The results are detailed in a study published on June 23 in the journal Chemical biology of nature And are an important step towards the discovery of new fungal drugs for cancer.
“The mushrooms have given us penicillin,” said Sherry Gao, co-author of the study and chemical and biomolecular engineer Upenn, in a press release. “These results show that many more drugs derived from natural products remain to be found.”
What is the “pharoahs” fungus of curse “?
Aspergillus flavus is one of the most frequently isolated mold species in agriculture and medicine. It is commonly found in the soil and can infect a wide range of important agricultural crops. The toxins of this fungus can cause pulmonary infections, especially in people with compromise immune systems. He bears the name of his dangerous yellow spores and has been considered a microbial villain for at least a century.
In the 1920s, after a team of archaeologists opened the tomb of King Tutankhamun near Luxor, Egypt, a series of premature deaths occurred among the excavation team. Rumors vulled a kind of curse from Pharoah. Doctors then theorized that the fungal spores that have been dormant for thousands of years could have played a role in death.
During excavations in the 1970s, a dozen scientists entered the tomb of Casimir IV in Poland. In just a few weeks, 10 of the researchers died. The surveys later revealed that the tomb contained the fungus A. Flavus.
A fatal fungus for a fatal disease
The same fatal fungus is now considered a potential treatment of cancer. Detailed therapy in this new study is a class of peptides or ripps modified by ribosomal and post-transduction. The name “Ripp” refers to the way the compound is produced. It begins in the ribosome – a small cellular structure that makes proteins – and is then modified by peptides or a laboratory intervention. In this case, the RIPP is modified to improve its properties killing cancer.
“The purification of these chemicals is difficult,” said the co-author of the study and doctoral comrade Upenn Qiuyue Nie.
While thousands of Ripp have already been identified in bacteria, only one handle has been discovered in mushrooms. One of the reasons of less discovery of Ripp Fongiques is that the former researchers probably malfuncted fungal Ripps like non -ribosomal peptides and did not understand very well 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.”
[ Related: College student discovers mysterious fungus that eluded LSD’s inventor. ]
Find mushrooms
To find more fungal ripps, the team first scanned a dozen strains of different Aspergillus Mushrooms. By comparing chemicals produced by these strains with known RIPP construction blocks, the team has identified A. Flavus As a promising candidate for an additional study.
Genetic analysis indicated a particular protein in A. Flavus as a source of fungal ripps. When the team has disabled the genes that create this protein, the chemical markers that indicated the presence of these RIPPs have also disappeared. The combination of metabolic and genetic information has identified the source of useful fungal RIPS in A. Flavus And could be used to find other fungal Ripps in the future.
The team then purified four different ripps. They found that the molecules all shared a unique structure of nested rings. The researchers appointed these molecules before not described after the fungus in which they were found: asperigimycins.
Even without genetic modifications, asperigimycins have demonstrated a medical potential when mixed with human cancer cells. Two of the four variants had powerful effects against leukemia cells.
The researchers added a fatty molecule called lipid to another variant and found that it had done as well as cytarabine and daunorubicin, two drugs approved by the FDA which have been used to treat leukemia for decades.
A gateway gene
Then the team wanted to understand why lipids improved the power of asperigimycins. To do this, the researchers selectively lit and deactivate the genes in leukemic cells. A gene (SLC46A3), turned out to be critical to allow aspérigimycins to enter leukemia cells in good quantity. The SLC46A3 gene helps materials to leave lysosomes, or tiny bags that collect foreign materials entering human cells.
“This gene acts like a bridge,” said Nie. “It doesn’t only help asperigimycins to get into cells, it can also allow other” cyclical peptides “to do the same.”
These chemicals have medicinal properties, just like asperigimycins. Nearly 24 cyclical peptides have received clinical approval since 2000 to treat cancer and lupus diseases, but many of them need modifications in order 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.
An additional experiment has shown that aspérigimycins probably disrupt the cellular division process.
“The cancer cells are divided uncontrollable,” said Gao. “These compounds block the formation of microtubules, which are essential for cell division.”
The compounds have had little or no effect on cancer cells in the breast, liver or lung or on a range of bacteria and fungi. According to the team, this suggests that the disruptive effects of asperigimycinas are specific to certain types of cells, which is a critical characteristic for any future medication.
Secrets of Nature’s Pharmacy
In addition to showing that asperigimycins have a future medical potential, the team has identified similar bunches of genes in other mushrooms. This means that more fungal RIPPS could be there.
“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 towards the potential of therapy, aspérigimycins must be tested in animal models, with the hope of one day spending regulated 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. ”
