An international team of scientists has proven that the natural plant chemical alstonine, which has shown promise in treating schizophrenia, can be produced by genetically modified yeast cells.
The advancement of using genetically engineered yeast cells to produce biological substances for medicinal purposes is yielding promising outcomes, as demonstrated by an international team of researchers engaged in fundamental research.
Notably, in 2022, these researchers garnered global recognition by orchestrating the creation of the longest biosynthetic pathway, akin to an ‘assembly line,’ within a microbial cell factory. This innovative design was specifically tailored to manufacture biological substances crucial for the development of cancer drugs.
Now, in an article published in the scientific journal Nature Chemical Biology, titled “Biosynthesis of natural and halogenated plant monoterpene indole alkaloids in yeast,” they presented their new findings on the artificial production of alstonine. This naturally occurring substance has demonstrated potential for treating mental disorders.
Michael Krogh Jensen, a senior researcher at DTU Biosustain and co-founder of the biotech company Biomia, emphasizes the widespread use of developing medicines from natural plant substances.
“However, since plants do not produce these substances to fight human diseases, there is often a need to modify them to make them more effective and safe.”
According to the team, the goal of the project is for the yeast platform to be a major tool in the discovery and advancement of plant-based therapy.
New research findings reveal the engineered yeast cells’ capability to produce additional alkaloids beyond vinblastine, a substance highlighted in their 2022 results. In addition to alstonine and serpentine, the researchers have expanded the method to create 19 new derivatives of these substances through halogenation, a chemical process widely employed in medicine development.
“We have found a method to make yeast cells use enzymes and carry out the same chemical process that takes place in halogenation. Plants generally can’t naturally carry out halogenation. Therefore, our versatile biotechnological platform is a possible method for optimizing and developing plant-based alkaloids that may then be used to make medicines against, for example, schizophrenia, for which there are many negative side effects such as insomnia, weight gain, and reduced immunity, when using existing medicines,” explains Michael Krogh Jensen.
The researchers established yeast-based cell factories by incorporating numerous genes from plants capable of biosynthesizing natural plant substances. Additionally, enzymes from bacteria were introduced to halogenate these natural substances, and the production was tested in yeast. After the conversion into serpentine and alstonine, the substances underwent purification. They conducted structural tests using Nuclear Magnetic Resonance spectroscopy (NMR) to analyze atomic composition and examined bioactivity in a monkey cell line.
Human trials have been initiated following a patent application for the manufacturing process. Biomia, the company established to commercialize the technology, raised $3 million in September 2023 for drug discovery based on the chemistry presented in the researchers’ Nature article from 2022 and the current study.
While the research into yeast-based production of halogenated, plant-inspired natural substances and their derivatives is in its early stages, the team is identifying potential candidates for treating mental disorders. These candidates will undergo preparation for clinical studies, with an optimistic projection by Michael Krogh Jensen to initiate clinical trials of substances derived from alstonine by 2026.
Despite promising results in clinical studies against schizophrenia or other mental disorders, it is anticipated that at least ten years will elapse before the research yields new medicines available for purchase at pharmacies.
Image Credit: iStock