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Origin: Deep Research Science
Author: Long Yanting
Guide
If it is possible to win the Nobel Prize if it has a solid scientific foundation and miraculous clinical efficacy, is it possible to win the Nobel Prize, but is it possible for GLP-1 drugs?
The answer is yes.
These GLP-1 drugs are everywhere in life – helping people manage their diabetes and hopefully reducing the risk of cardiovascular disease and even one day curing drug and alcohol addiction.
Randy Seeley, director of the Michigan Center for Nutritional Obesity Research, believes that "there is no doubt that these drugs, both in terms of what they have achieved and their potential, are huge and deserve to be considered for important awards."
Then the new question arises, if the GLP-1 drug wins the award, then who should be the winner?
In May, Novo Nordisk announced the takedown of all TV commercials for the weight loss drug Wegovy.
Not because of any negative news or vicious competition, but because the drug is so popular, the pharmaceutical company said: there is no need to advertise at all.
Admittedly, Wegovy is a microcosm of the global popularity of GLP-1 drugs. As a class of drugs used to treat diabetes, GLP-1 drugs have been widely used in diabetes, weight loss, alcohol addiction control and other fields, and have become a veritable "top stream" in the drug industry, and many people even think that winning the Nobel Prize is not an exaggeration.
However, these sensational drugs didn't happen overnight. From the discovery of the GLP-1 hormone to the treatment of diabetes and then to obesity, the process was long and tortuous, lasting more than four decades and involving hundreds of researchers from academia and the pharmaceutical industry.
If we had to identify the heroes of early GLP-1 drug discovery and research, let's trace the GLP-1 drug discovery journey.
Svetlana Mojsov, Joel Habener, and Dan Drucker (from left to right) at Massachusetts General Hospital and Jens Juul Holst from the University of Copenhagen present early insights into the structure and function of GLP-1.
01
Richard Goodman: The discoverer of GLP-1
In the 70s of the 20th century, scientists in Boston and California set off a revolution in genetic research. They have developed a groundbreaking new technology that not only enables the isolation of genes, but also provides insight into how genes work.
At that time, they used new technology to make it possible to convert mRNA (the information that cells use to produce proteins) into DNA, which could then be sequenced and even inserted into bacteria, creating biomolecule factories. As long as you have a large amount of mRNA, a process that would have taken six months to complete can now be easily done in an afternoon.
The promise of bringing physiological processes to molecular resolution was an instant boom in biomedical research laboratories across the country.
The laboratory where the Massachusetts General Hospital works is one of the meccas where the technique is applied to study hormones. In 1979, Richard Goodman, a researcher in the laboratory, removed dozens of lump bean-sized pieces of meat from the tissue surrounding the intestines of fish. These pieces of meat are mysterious, with a large number of cells containing DNA copies of the instructions for making metabolic hormones.
Goodman's postdoctoral fellow, P. Kay Lund. Kay Lund) is also interested in intestinal peptides, having identified for the first time the genetic sequence of glucagon precursors, a hormone that increases blood sugar, using Goodman's bacterial library containing fish DNA.
In a paper published in 1982, they noted that the glucagon precursor gene actually contains the code for three peptides: glucagon, two novel hormones expressed in the gut.
A year later, a team led by Graeme Bell cloned and sequenced versions in humans and other mammals at the Chiron Corporation in California, which they named GLP-1 and GLP-2, which stand for glucagon-like peptides 1 and 2.
Later, a Danish scientific team tried to synthesize the GLP-1 hormone and inject it into the isolated pancreas of live pigs to test its effect. However, this attempt was not successful, as the injection of GLP-1 did not show the expected reaction.
Faced with failure, they turned to their colleague Thue Schwartz, who was doing postdoctoral research in the laboratory of Donald Steiner at the University of Chicago in the United States and became familiar with peptide synthesis techniques. Working with Schwartz, they discovered a hormone called pancreatic polypeptide that has a special breakdown pattern. They believe that a similar situation could happen with GLP-1.
Based on data from both groups of scientists, GLP-1 is starting to look like it has the potential to treat diabetes. To test this potential, they decided to conduct more trials, including the application of GLP-1 in humans. In the summer of 1987, the Danish team leader attended a party with Stephen Bloom, an endocrinologist who was working at Hammersmith Hospital at the time. At the party, they discussed the therapeutic potential of GLP-1.
Soon, though, the research went to a hard time: in clinical trials, the researchers learned that GLP-1 is a very short-lived substance. Enzymes in the blood break it down within minutes. Therefore, a large amount of GLP-1 is needed to treat diabetes, but too much GLP-1 can make patients feel nauseous and vomit.
Solving this problem means creating molecules that resemble GLP-1 but are more durable than natural counterparts.
02
Exendin-4: a longer-lasting molecule than GLP-1
In 1977, Rosalyn Sussman Yalow was awarded the Nobel Prize for her work on the development of a radioimmunoassay method, a revolutionary method for measuring peptides in the blood.
Her lab has a talented researcher, John Eng, who specializes in using the latest techniques to isolate peptides and determine their structure.
In 1983, young gastroenterologists Jean-Pierre Raufman and Enger joined forces to extract a 39-amino acid peptide from the venom of the Goral lizard and named it exendin-4.
Exendin-4 is a scientifically new discovery, and its shape is almost identical to that of GLP-1. The difference with GLP-1 is that GLP-1 degrades in the blood in less than a minute, while Exendin-4 remains active for more than two hours. Rofman's experimental team thought it was a potential diabetes drug formulation.
But for the '90s, the discovery was a bit ahead of its time. "We presented it at the conference at the time, but not many people were interested. Rogman said.
Even the Department of Veterans Affairs, where Enge worked, was reluctant to use departmental resources to patent Exendin-4. Eventually, Enge took care of the paperwork himself. After the patent was issued, he tried to arouse the interest of the large diabetes pharmaceutical companies of the time, but the opportunity was rejected by all the companies.
The reason is simple, no one wants to inject something from the mouth of a deadly lizard into a patient.
Rogman disagreed, "Pharmaceutical companies need to take a risk and realize that there is something in the venom."
In 2005, the FDA approved exenatide, a drug marketed under the name Byetta for the treatment of diabetes, and was a huge success once it was marketed, affectionately known as "Lizzie" or "Gilly" by some users in honor of its reptilian-derived lizard peptide.
Time will tell, and perhaps Rovman is right.
03
How GLP-1 drugs are entering the field of obesity drugs
At the same time, the Danish pharmaceutical company Novo Nordisk is also developing its own GLP-1 receptor agonist, which they have named liraglutide, and they want to apply the drug to a broader field - obesity.
Inside Novo Nordisk, a cell biologist noticed that tumors in mice secreted GLP-1 and caused the mice to have a decreased appetite.
After years of research, Novo Nordisk has finally developed a viable drug design that adds long fat chains to GLP-1-like molecules to increase its duration while being reversible so that it can bind to GLP-1 receptors. This successful molecule, named liraglutatide, entered clinical testing in 2000 as an injectable drug for the treatment of diabetes.
In addition to boosting insulin secretion, this drug also reduces appetite, making it a dual-function drug for treating diabetes and weight loss.
Soon, the research team updated another version, semaglutide. Liraglutide has been shown to reduce a person's food intake by up to 15%, while simaglutide can reduce by up to 35%.
Eventually, liraglutide was approved by the FDA in 2010 to be marketed under the name Victoza. In 2021, saxaglutide was approved under the name Wegovy.
Although the exact mechanism of Wegovy is still not fully understood, the weight-loss effect of this drug is already very clear. It has sparked an "explosive" demand around the world, and even led to drug shortages at one point.
As of 2022, the number of prescriptions for Wegovy, Ozempic and similar obesity drugs in the United States has reached 9 million, which shows their importance in the field of obesity management.
04
Next split: glucagon
Many believe that the subsequent development of GLP-1 may be based on the work of Matthias Tschöp and Richard DiMarchi.
Matthias Tschöp(左)和 Richard DiMarchi(右)
In 1999, the young German doctor Zschup was working as a postdoctoral fellow. At the time, leptin was a highly anticipated obesity treatment, but clinical trial results were disappointing.
In the course of their research, Tsserp and his colleagues discovered the new hormone ghrelin, which causes an increase in appetite. However, attempts to block ghrelin were unsuccessful. Tschep recognizes that targeting a single hormone alone may not be sufficient to effectively treat obesity.
In 2003, Tscheup received a call from Dimad, an experienced peptide chemist who had worked on endocrine research, and they decided to collaborate on the development of a treatment for obesity.
At first, they started looking for different hormone targets, one of which was glucagon, a hormone that has been linked to raising blood sugar. However, they found that activating glucagon receptors actually led to weight loss, contrary to conventional wisdom, as glucagon inhibition is often thought to be needed to lower blood sugar.
So they turned to another hormone, GIP, which is involved in insulin secretion and blood sugar regulation. They tried to activate the GIP receptors and found that this method had a positive effect on weight loss.
Eventually, they combined their research on these two hormones with another hormone, GLP-1, to create drugs that target GLP-1, glucagon, and GIP receptors simultaneously.
It's an appetite-suppressing hormone, but it's not easy to make sure that one molecule can activate three different receptors at the same time. However, Tschep and Dimadchi succeeded in creating this triple agonist and proved it to be more powerful than previous double agonists in experiments.
While these findings were controversial for a time, it is undeniable that more and more companies are now developing combination agonist drugs to achieve greater weight loss. In the future, perhaps this will become a new outlet for the development of GLP-1 drugs.
参考资料GLP-1 drugs are transforming diabetes, obesity and more. Could a Nobel be next?