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<\/a>By merging elements of 4 totally different hormones right into a single drug, researchers purpose to fight weight problems whereas additionally tackling associated circumstances corresponding to sort 2 diabetes, most cancers, and cardiovascular disease<\/span>. More than 15 million adults in the United States, representing about 4.5% of the population, are currently prescribed weight loss medications such as Ozempic and Wegovy. These treatments have shown strong results, but they also come with significant limitations. Once patients stop taking them, the weight loss effects often fade, and potential risks like bone loss, muscle reduction, and persistent nausea have raised concerns about their long-term safety. The nausea in particular can make it difficult for many people to continue treatment.<\/p>\n In response to these challenges, a research team at Tufts University<\/a>, led by Krishna Kumar, Robinson Professor of Chemistry, has developed a new type of compound that they hope will deliver better outcomes with fewer negative effects. Their findings were published in the Journal of the American Chemical Society<\/em>.<\/p>\n Most existing drugs in this area are designed to act on one, two, or sometimes three hormone receptors that influence glucose metabolism and appetite. The Tufts researchers, however, have uncovered a fourth receptor that could be added to the mix, potentially offering a more powerful and balanced approach to managing weight.<\/p>\n \u201cObesity is linked to over 180 different disease conditions, including cancer, cardiovascular disease, osteoarthritis, liver disease, and type 2 diabetes, and affects over 650 million people worldwide,\u201d said Kumar. \u201cWhat drives us is the idea that we can design a single drug to treat obesity and simultaneously mitigate the risk of developing a long list of health problems plaguing society.\u201d<\/p>\n After we eat a meal, our gut and brain trigger a hormonal \u201cfuel gauge\u201d that regulates levels of glucose and tells us when we have had enough to eat.<\/p>\n The hormone glucagon-like peptide 1 (GLP-1) is released to help stimulate the production of insulin<\/span> and the uptake of glucose in muscle and other tissues. With the cells now loaded with fuel, the level of glucose in the blood returns to normal. Ozempic uses GLP-1 with slight modifications to increase its availability in the bloodstream. Its success in controlling blood glucose has prompted the American Diabetes Association to recommend it and other GLP-1-based drugs as the new first line injectable treatments for diabetes, ahead of insulin.<\/p>\n But GLP-1 also acts directly on the brain, making us feel full after having a meal, and it slows down the rate that the stomach contents are emptied into the intestines, creating a more evenly paced release of nutrients and glucose into the bloodstream. That\u2019s why it has also become extremely popular as a weight loss treatment.<\/p>\n It\u2019s still not a perfect drug strategy for weight loss, though. \u201cThe 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,\u201d said Kumar. \u201cAs much as 40% of people using these drugs give up after the first month.\u201d<\/p>\n A second hormone released after eating is glucose-dependent insulinotropic peptide (GIP). It also makes us feel full after a meal. GIP looks a lot like GLP-1, so rather than administer two drugs, researchers created one peptide that incorporates structural elements of both\u2014what\u2019s called in drug development a chimera. That drug, called Mounjaro or Zepbound (the brand names for tirzepatide), has the added benefit of significantly reducing nausea. As a more tolerable treatment, it may overtake Ozempic in the weight loss market.<\/p>\n \u201cAnd then there is a third hormone, glucagon,\u201d said Kumar. \u201cParadoxically, it actually increases blood glucose, but at the same time increases the expenditure of energy in cells of the body, raises body temperature, and suppresses appetite.\u201d By adding glucagon to the mix, GLP-1 and GIP end up neutralizing its glucose-enhancing effect, leaving the remaining functionalities of all three hormones working together to enhance weight loss.<\/p>\n Glucagon is also similar in structure to GLP-1 and GIP, so drug developers created a single chimera peptide that incorporates elements of all three hormones, which can be recognized by their three separate receptors. That drug, called retatrudide, is currently in clinical trials that indicate even greater achievable weight loss (up to 24%) compared to the original GLP-1 drugs (6-15%).<\/p>\n \u201cThe goal that people are trying to shoot for is bariatric surgery,\u201d said Kumar. That\u2019s a surgical procedure significantly reducing the size of the stomach, which can achieve long-lasting weight loss up to 30%. \u201cFor individuals with persistent obesity and potential deadly associated conditions, it becomes a necessary but invasive treatment.\u201d<\/p>\n Current injectable weight loss drugs still fall short of that gold standard, so the Tufts chemists are focused on a drug redesign that could match the 30% weight loss outcome.<\/p>\n \u201cThere is one more hormone we wanted to bring in to complete a weight control quartet,\u201d said Tristan Dinsmore, a graduate student in the Kumar lab and the lead author of the study. \u201cIt\u2019s called peptide YY (PYY). This molecule is also secreted by the gut after we eat a meal, and its job is to reduce appetite and slow the process of emptying food from the stomach, but via different mechanisms than either GLP-1 or GIP. It may also be involved in directly \u2018burning off\u2019 fat.\u201d<\/p>\n PYY is from a separate and structurally unrelated class of hormones than the first three, so blending its structure into a chimeric peptide that also mimics GLP-1, GIP, and glucagon was not easy. Instead, the Tufts team was able to join two peptide segments end-to-end, creating a new \u2018tetra-functional\u2019 clinical candidate.<\/p>\n \u201cOne of the limitations of the current drugs is that individual variation, possibly including how people express target receptors or respond to their corresponding hormones, can lead to lesser than desired weight loss outcomes in many patients,\u201d said Martin Beinborn, visiting scholar in the Department of Chemistry. \u201cBy hitting four different hormone receptors at the same time, we hope to improve the chances of averaging out such variation toward the goal of achieving greater and more consistent overall effectiveness.\u201d<\/p>\n \u201cA second issue is that patients tend to regain weight after discontinuing currently available GLP-1 related drugs,\u201d said Beinborn, who notes that lifestyle changes should ideally be a complement to medication treatment. This two-pronged approach will not only support reaching and keeping one\u2019s target weight, but may also help preserve bone and muscle mass.<\/p>\n \u201cRecent studies indicate that weight rebound after drug discontinuation is delayed with the newer, more effective GLP-1 mimetics,\u201d he said. \u201cExtending from this observation, one may speculate that multi-chimeras along the lines of the one we discovered could get us closer to the bariatric surgery standard of lasting weight loss.\u201d<\/p>\n Reference: \u201cMolecular Design of Unimolecular Tetra-Receptor Agonists\u201d by Tristan C. Dinsmore, Jacob E. Cortigiano, Siyuan Xiang, Marina V. Spenciner, Alexandra R. Dobbins, Richard L. Zhao, Brett M. Waldman, Martin Beinborn and Krishna Kumar, 3 June 2025, Journal of the American Chemical Society<\/i>. Funding: National Institutes of Health<\/span><\/p>\n Never miss a breakthrough: Join the SciTechDaily newsletter.<\/a><\/b><\/p>\n<\/p><\/div>\n
<\/strong><\/p>\n<\/a>How the Drugs Work<\/h4>\n
<\/a>Going for the Weight Loss Gold Standard with a Fourth Target<\/h4>\n
DOI: 10.1021\/jacs.5c04095<\/a><\/p>\n