Tufts University chemists have designed a new compound that could advance the next generation of weight loss drugs by combining the effects of four appetite- and metabolism-related hormones. The approach aims to improve weight loss outcomes and address related health risks such as type 2 diabetes, cancer and heart disease.
“What 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,” said Krishna Kumar, senior author and Robinson Professor of Chemistry.
Current injectable treatments like Ozempic and Wegovy target a single hormone called GLP-1. Others, such as tirzepatide (sold under the brand names Mounjaro and Zepbound), combine GLP-1 with GIP to reduce nausea and improve outcomes. The Tufts team added two more targets to the mix: glucagon and peptide YY (PYY).
“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. “As much as 40% of people using these drugs give up after the first month.”
By mimicking all four hormones in one molecule, the team hopes to create a drug that works more like the body’s natural hormonal response to food.
“There is one more hormone we wanted to bring in to complete a weight control quartet,” said Tristan Dinsmore, a graduate student and lead author of the study. “It’s 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 ‘burning off’ fat.”
The result is a new “tetra-functional” peptide, or unimolecular drug that acts on four separate receptors at once.
“One 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,” said Martin Beinborn, visiting scholar in the Tufts Department of Chemistry. “By 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.”
Beinborn added that weight rebound after discontinuing GLP-1 drugs remains a concern: “Extending 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.”
The study was published in the Journal of the American Chemical Society. The compound has not yet been tested in human trials. This research was supported by the National Institutes of Health, which funds studies aimed at improving public health through scientific discovery.