Tufts researchers report experimental ‘four‑in‑one’ peptide that produced larger weight loss in preclinical tests

Tufts University researchers reported the development of an experimental peptide that simultaneously targets four hormone pathways involved in appetite and metabolism and produced larger weight‑loss effects with fewer reported adverse effects in preclinical studies, according to a paper published in the Journal of the American Chemical Society.

The team said the molecule engages receptors for GLP‑1, GIP, glucagon and peptide YY (PYY), an approach the authors described as nudging four “dimmer switches” that together regulate hunger, satiety, blood sugar and energy use. The authors cautioned the drug remains in early development and has not been tested in human clinical trials.

Lead author Tristan Dinsmore, a graduate student in the Kumar laboratory, said the team constructed a single experimental peptide intended to mimic the combined effects of multiple gut hormones without overstimulating any one pathway. "We built a single experimental peptide that works like four hormones at once, so we're not pushing one button too hard," Dinsmore said. "Instead, we're nudging four 'dimmer switches' together... [It helps to] balance things out."

Krishna Kumar, a professor of chemistry who led the research, described the design as an attempt to improve tolerability compared with existing GLP‑1 receptor agonists such as semaglutide (marketed as Ozempic and Wegovy), which are known to induce nausea in many patients. "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. He and colleagues said substantial numbers of patients discontinue treatment because of side effects.

Current widely prescribed antiobesity medications include single‑pathway GLP‑1 agonists and dual‑agonists such as tirzepatide (sold as Mounjaro and Zepbound), which activate both GLP‑1 and GIP receptors. A separate molecule in clinical development, retatrutide, targets three hormone pathways. The Tufts team said adding PYY to the mix presents additional mechanisms for reducing appetite and slowing gastric emptying, and that PYY may also promote fat burning through pathways distinct from the other hormones.

Co‑author Martin Beinborn, a visiting scholar in the chemistry department, said the multi‑receptor approach may reduce variability in response. "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," he said.

The Tufts paper reports that the experimental peptide produced weight‑loss effects in laboratory models that the authors described as more than twice those observed with GLP‑1–only drugs in comparable preclinical settings, and with fewer overt signs of nausea. The study did not include human participants, and the authors and other experts emphasize that safety and efficacy must be established in clinical trials before the compound could be considered for use in patients.

Interest in new obesity medicines has surged as GLP‑1 receptor agonists have been widely prescribed. Estimates cited by the researchers put current use of GLP‑1–based weight‑loss drugs at more than 15 million adults in the United States, about 4.5 percent of the population. Prescription drugs have offered substantial weight reductions for many patients: reported averages vary by compound, with some GLP‑1 agents associated with typical losses in the range of about 10 to 15 percent of body weight and dual‑agonists reporting higher averages in some trials. Bariatric surgery remains the most effective intervention for sustained, large‑magnitude weight loss in clinical studies, with typical excess weight loss after surgery exceeding what is usually reported with medications.

Despite effectiveness in trials, clinicians and regulators have highlighted uncertainties about long‑term safety, tolerability and durability of effect. Common adverse effects of GLP‑1–class drugs include nausea and other gastrointestinal symptoms; some case reports and observational studies have linked use with dental problems, changes in vision, hearing complaints, and mood effects, but regulators including the U.S. Food and Drug Administration have not established a direct causal link for many reported conditions. Evidence also indicates that stopping therapy is often followed by weight regain for many patients, with researchers noting that a substantial portion of lost weight is commonly regained within a year after discontinuation as hormone levels return toward baseline.

The Tufts team said further preclinical work and safety testing will be needed before any human studies can begin. The authors noted that combining molecules from distinct structural classes presented formulation and design challenges, and that the reported results reflect early successes in addressing those obstacles.

Outside experts cautioned that promising preclinical effects do not always translate to human benefit and that rigorous clinical trials are necessary to determine appropriate dosing, side‑effect profiles and long‑term outcomes. The Tufts study adds to a growing research effort to develop multi‑targeted pharmacologic approaches to obesity that could broaden treatment options while aiming to minimize the adverse effects that limit adherence to current therapies.

The study appears in the Journal of the American Chemical Society; the authors said they plan additional studies to evaluate safety, pharmacology and the potential for clinical development.