Scientists develop a 4 in 1 drug for weight loss with fewer side effects

By merging components of four different hormones into a single drug, researchers aim to fight obesity while attacking related conditions such as type 2 diabetes, cancer and cancer and cancer, cancer and cancer cardiovascular disease.

In the United States, more than 15 million adults, representing approximately 4.5% of the population, are currently prescribed on weight loss drugs such as Ozempic and Wegovy. These treatments have shown high results, but they also have important limits. Once patients stop taking them, weight loss effects often fade and potential risks such as bone loss, muscle reduction and persistent nausea have raised worries about their long -term safety. Nausea in particular can make it difficult for many people to continue treatment.

In response to these challenges, a research team from TUFTS University, led by Krishna Kumar, Robinson’s chemistry professor, has developed a new type of compound which, hopefully, will provide better results with fewer negative effects. Their results were published in the Journal of the American Chemical Society.

Most existing drugs in this area are designed to act on one, two or sometimes three hormonal receptors that influence glucose and appetite metabolism. TUFTS researchers, however, discovered a fourth receiver that could be added to the mixture, potentially offering a more powerful and balanced approach to manage weight.

“Obesity is linked to more than 180 different diseases, including cancer, cardiovascular disease, osteoarthritis, liver disease and type 2 diabetes, and affects more than 650 million people worldwide,” Kumar said. “What motivates us is the idea that we can design a single drug to treat obesity and simultaneously alleviate the risk of developing a long list of health problems that afflict society.”

How do medications work

After eating a meal, our intestine and our brain trigger a hormonal “fuel gauge” that regulates glucose levels and tells us when we had enough to eat.

The peptide 1 of the hormone type (GLP-1) is released to help stimulate the production of insulin and the absorption of glucose in muscles and other fabrics. With the cells now loaded with fuel, the level of glucose in the blood amounts to normal. Ozempic uses GLP-1 with slight modifications to increase its availability in the bloodstream. Its success in the control of blood sugar has prompted the American Diabetes Association to recommend it and other drugs based on GLP-1 as new injectable first-line treatments for diabetes, in front of insulin.

But GLP-1 also acts directly on the brain, making us feel full after having a meal, and it slows down the rate that stomach content is emptied in the intestines, creating a release of nutrients and glucose more uniformly punctuated in the bloodstream. This is why it has also become extremely popular as a weight loss treatment.

It is still not a perfect drug strategy for weight loss. “The biggest problem with GLP-1 drugs is that they have to be injected once a week, and they can induce a very strong feeling of nausea,” Kumar said. “Up to 40% of people who consume these drugs abandon after the first month.”

A second hormone released after eating is the insulinotropic peptide dependent on glucose (GIP). It also makes us feel full after a meal. GIP is very similar to GLP -1, so rather than administering two drugs, the researchers have created a peptide which incorporates structural elements of the two – which is called in the development of drugs a chimera. This medication, called Mounjaro or Zepbound (brand names of shooting), has the additional advantage of considerably reducing nausea. As a more tolerable treatment, it can exceed ozempic on the weight loss market.

“And then there is a third hormone, glucagon,” said Kumar. “Paradoxically, it actually increases blood sugar, but at the same time increases energy expenditure in body cells, increases body temperature and removes appetite.” By adding glucagon to the mixture, GLP-1 and GIP end up neutralizing its effect improving glucose, leaving the remaining features of the three hormones working together to improve weight loss.

Glucagon is also similar in the GLP-1 and GIP structure, so drug developers have created a single chimera peptide which incorporates elements of the three hormones, which can be recognized by their three distinct receivers. This medication, called Retacatrude, is currently in clinical trials which indicate an even greater weight loss (up to 24%) compared to the original GLP-1 drugs (6-15%).

Go for the weight loss stallion with a fourth target

“The goal for which people are trying to shoot is bariatric surgery,” said Kumar. It is a surgical procedure considerably reducing stomach size, which can reach lasting weight loss up to 30%. “For people with persistent obesity and potential deadly conditions, it becomes a necessary but invasive treatment.”

Current injectable weight loss drugs are still below this ordered stallion, so that tuft chemists are focused on a medication overhaul that could correspond to the result of weight loss of 30%.

“There is another hormone that we wanted to bring to complete a weight control quartet,” said Tristan Dinsmore, a graduate student from the Kumar laboratory and the main study of the study. “This is called the YY peptide (PYY). This molecule is also secreted by the intestine after eating a meal, and its work consists in reducing appetite and slowing down the process of emptying stomach food, but via different mechanisms that GLP-1 or GIP.

Pyy comes from a separate and structurally unrelated class of hormones that the first three, therefore mixing its structure into a chimerical peptide which also imitates GLP-1, GIP and Glucagon was not easy. Instead, the TUFTS team was able to reach two segments of end-to-end peptides, creating a new “Tetra-Functional” clinical candidate.

“One of the limits of current drugs is that individual variation, perhaps including the way people express target receptors or react to their corresponding hormones, can lead to lower results than desired weight loss in many patients,” said Martin Beinborn, a scholarly learned to the Department of Chemistry. “By hitting four different hormone receivers at the same time, we hope to improve the chances of making such a variation towards the objective of reaching greater and more coherent overall efficiency.”

“A second problem is that patients tend to regain weight after stopping drug-related drugs currently available,” said Beinborn, who notes that lifestyle changes should ideally be a complement to the treatment of drugs. This two -stea approach will not only support the damage and maintenance of its target weight, but can also help preserve bone and muscle mass.

“Recent studies indicate that the weight of weight after stopping the drug is delayed with the latest and more effective GLP-1 mimetics,” he said. “Extending from this observation, we can assume that the multi-chests on the meaning of that which we discovered could bring us closer to the standard of bariatric surgery of lasting weight loss.”

Reference: “Molecular conception of unimolecular tetra receptor agonists” by Tristan C. Dinsmore, Jacob E. Cortigiano, Siyuan Xiang, Marina V. Spancin, Alexandra R. Dobbins, Richard L. Zhao, Brett M. Waldman, Martin Beinborn and Krishna Kumar, June 3, 2025 Journal of the American Chemical Society.
Two: 10.1021 / jacs. 5C04095

Funding: National Health Institutes

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