Highly toxic plant-based weight loss drug can now be produced from yeast

In China, children are taught to avoid this plant. The plant, Thunder God Vine (Chinese: 雷公藤), which in China has earned the nickname “Seven Steps to Death”, is so poisonous that a person risks death just a few steps after consuming it .

But despite its deadly nature, thunder god vine (Tripterygium wilfordii) also hides something very beneficial for us humans. In its roots, the plant produces the compound cecistrol, a chemical agent with powerful anti-obesity properties.

Experiments using mice fed a high-fat diet showed that mice given Celastrol gained 45% less weight than the control group. Experiments with human cells showed similar effects.

This effect is due to the fact that Celastrol reactivates the body’s sensitivity to leptin, a hormone to which overweight people become resistant. Leptin is one of the hormones that causes the body to burn more calories and thus regulate weight.

How do you get your hands on the “right” stuff without the toxicity that usually accompanies it? That is the question.

“For obvious reasons, a person cannot simply eat the plant and benefit from the medicine. So what to do? The problem with extracting Celastrol from the natural source is that it is very difficult to separate it from other toxic molecules that the plant contains. Until now, there is no effective method to achieve this,” says Sotirios Kampranis, professor at the Department of Plant and Environmental Sciences.

Yeast as a “surrogate mother”

In tackling the problem, the research team from the Department of Plant and Environmental Sciences sought to find a way to produce this substance biotechnologically. Led by Assistant Professor Yong Zhao, the researchers were the first to map the pathway with the 15 biochemical steps the plant undergoes during the formation of cecistrol. These steps are essential to know in order to recreate the substance through biosynthesis. Their work was published in Natural chemistry.

“We discovered how the plant forms çastrol by studying every step of the manufacturing process. This means we could take the genes and enzymes that make the substance and introduce them into another organism that doesn’t produce toxic substances. And that’s what we’re done with with yeast,” says Yong Zhao.

The researchers were able to produce synthetic Celastrol in a tank with ordinary yeast used as the host organism in which the substance was produced.

“Imagine, you just feed the çastrol molecule with table sugar, and in doing so you get a compound that is almost in pure form, without the toxic compounds that otherwise accompany it in nature. The process is simple and effective – it only takes about a week to get the final product. And this is done without the toxic solvents and catalysts usually used in chemical syntheses. I think there is enormous potential here,” says Sotirios Kampranis .

The greenest and only method

Today, most pharmaceuticals are created synthetically from crude oil-based petrochemicals. And traditional methods of developing synthetic drugs aren’t even an option, as Yong Zhao explains:

“As the Celastrol molecule is very complex, there are currently only very inefficient chemical synthesis methods that are not applicable to large-scale production. Our method is therefore not only a green method, it is also the only real method that exists.”

The researchers point out that yeast is widely used in the biotechnology industry, where there is all the know-how and infrastructure needed to produce çastrol on a large scale.

“This is precisely why we chose to use yeast as an organism. As academics develop the technology, it is important that it comes in a form useful to industry, where the technology can be further developed to making products that can help us all,” says Sotirios Kampranis.

The next step will be to more closely study the drug’s potential in treating obesity in humans. Researchers hypothesize that a potential treatment may be carried out with Celastrol alone or in combination with other therapies.

“For example, we can imagine a treatment where Celastrol would be combined with other anti-obesity drugs to obtain a more robust effect. Because the more targets in the body that are affected, the better. Indeed, we often see a synergistic effect when several “Agents are in play simultaneously. But here, of course, the pharmaceutical industry has to take over,” says Yong Zhao.

The University of Copenhagen has filed a patent application for the invention and is currently in talks with potential partners about commercializing the method.

How the medicine works

Some people are able to eat a lot without gaining weight because our metabolism knows when we are eating a lot and secretes certain hormones that make us burn more calories. One of these hormones is leptin.

Overweight people become resistant to leptin due to overproduction of the hormone, leading to inflammation of the hypothalamus. The body therefore does not receive the signal. Celastrol resensitizes the body to leptin.

Thunder God Vine

The plant, Thunder God Vine, called Tripterygium wilfordii in Latin, has been used for thousands of years in traditional Chinese medicine to treat rheumatoid arthritis and as a contraceptive.

The plant grows in the mountainous regions of southern China, where it is collected by local collectors. So, in addition to being extremely toxic, it is also difficult to find.

“The compound is extracted from the root of the plant. And the plant takes at least three years to grow large enough to be harvested. Therefore, an entire plant must be sacrificed to acquire the medicine. So it is not a tenable method.” » underlines Sotirios Kampranis.