Scientists have reported a new way to produce the chemotherapeutic agent etoposide, and they believe this discovery could lead to a more stable supply of the drug.
Currently, producing etoposide requires isolating one of its precursors, (–)-podophyllotoxin, from the endangered, slow-growing, Himalayan Mayapple plant (Podophyllum hexandrum).
But researchers found they could generate the immediate precursor to etoposide—(–)-4’-desmethyl-epipodophyllotoxin—in a more easily accessible, faster-growing tobacco plant (Nicotiana benthamiana).
Elizabeth Sattely, PhD, of Stanford University in California, and her graduate student, Warren Lau, described this work in Science.
The pair noted that there are 4 known genes behind (–)-podophyllotoxin production, but the full recipe for this compound has eluded researchers, in part because of the Mayapple’s immense genome.
To tap into the Mayapple’s chemotherapeutic potential, Lau and Dr Sattely first focused on the 4 known genes—PLR, SDH, CYP719A23, and DIR. Then, they analyzed RNA sequencing data from the Mayapple to identify similar genes.
Next, the pair manipulated the tobacco plant to express multiple gene candidates at once and identified the resulting compounds in leaf tissue using mass spectrometry.
Dr Sattely and Lau identified 6 new genes—OMT3, CYP71CU1, OMT1, 2-ODD, CYP71BE54, and CYP82D61.
These genes, when expressed with the original 4, produce the immediate etoposide precursor (–)-4′-desmethyl-epipodophyllotoxin, which outperforms (–)-podophyllotoxin as a chemotherapy ingredient.
The researchers said this work has revealed a simpler and more direct route to etoposide that circumvents the semisynthetic epimerization and demethylation required to produce etoposide from (–)-podophyllotoxin.
However, Dr Sattely said the eventual goal is to use yeast instead of plants to produce etoposide. Yeast can be grown in large vats and may therefore provide a more stable source of drugs.
In addition, yeast provides the opportunity to modify genes to produce proteins with slightly different functions. And it may be possible to feed the yeast a slightly different starting product, thereby changing the chemical a molecular assembly line churns out.
These approaches could provide a way of tweaking existing drugs in an effort to improve them.
