A team of researchers from the University of Pennsylvania transforming Aspergillus flavus, a toxic fungus historically associated with mysterious deaths in ancient tombs, into a powerful anticancer compound.
Aspergillus flavus, named for its dangerous yellow spores, has a notorious history linked to archaeology. It has been associated with the so-called "pharaoh's curse" following the excavation of King Tutankhamun's tomb, where members of the team experienced a series of untimely deaths. Decades later, doctors theorized that dormant fungal spores like Aspergillus flavus could have contributed to these deaths. In the 1970s, a similar incident occurred when scientists entered the tomb of Casimir IV in Poland. Within weeks, ten out of twelve researchers died. Subsequent investigations revealed that the tomb contained Aspergillus flavus, whose toxins can lead to lung infections, especially in people with compromised immune systems.
The scientists isolated a new class of molecules from Aspergillus flavus, naming them asperigimycins after the fungus in which they were found. Testing revealed that two of the four variants of asperigimycins had strong effects against leukemia cells without any modifications, according to a press release published on EurekAlert.
A variant to which the researchers added a lipid performed comparably to cytarabine and daunorubicin, two FDA-approved drugs that have been used for decades to treat leukemia.
An aspect of the discovery is the specificity of these compounds. The asperigimycins had little to no effect on breast, liver, or lung cancer cells, nor on a range of bacteria and fungi. The specificity is a crucial characteristic for any future medication.
Sherry Gao, a study co-author and Presidential Penn Compact Associate Professor in Chemical and Biomolecular Engineering at the University of Pennsylvania, expressed optimism about the potential of natural products in medicine. "Fungi gave us penicillin. These results show that many more medicines derived from natural products remain to be found," Gao said, according to Popular Science.
The preparation of this article relied on a news-analysis system.
The researchers discovered that asperigimycins disrupt the process of cell division by blocking the formation of microtubules, which are essential for cell division. "Cancer cells divide uncontrollably," Gao explained.
To understand why lipids enhanced the potency of asperigimycins, the team conducted additional experiments. They found that a specific gene, SLC46A3, plays an essential role in the efficacy of the treatment. "This gene acts as a gateway. It not only helps asperigimycins penetrate cells, but it may also allow other cyclic peptides to do the same," said Qiuyue Nie, the principal researcher of the study, according to EurekAlert. Nie added, "Knowing that lipids can affect how this gene transports chemicals into cells gives us another tool for drug development."
The study's findings suggest that more fungal RiPPs—ribosomally synthesized and post-translationally modified peptides—remain to be discovered. The researchers identified similar clusters of genes in other fungi, suggesting many more of these compounds remain to be discovered. "Even though only a few have been found, almost all of them have strong bioactivity. This is an unexplored region with tremendous potential," Nie remarked, as reported by EurekAlert.
"Nature has given us this incredible pharmacy. It's up to us to uncover its secrets. As engineers, we're excited to keep exploring, learning from nature, and using that knowledge to design better solutions," Gao said.
The study was published in the journal Nature Chemical Biology.