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By science journalist Antje Gerd Poulsen

When obesity threatens health, many benefit from the current appetite regulating drugs that curb the urge to raid the fridge. But for some, the weight loss comes at a cost: nausea, vomiting, and bloating can occur, and in some cases, too much muscle mass is lost along with the fat.

These challenges are what PhD Asli Shenol from the University of Copenhagen wants to solve with a new weight-loss drug that targets a previously overlooked receptor in the brain’s appetite control center.

“Our preliminary studies suggest that we can achieve a synergistic effect with the current appetite regulating agents, so appetite is suppressed more effectively,” she explains.

Asli Shenol is a postdoc in professor Thue W. Schwartz’s lab at the NNF Center for Basic Metabolic Research at the University of Copenhagen, and she has just received a Frontier Grant from the Lundbeck Foundation to develop the drug and present it to potential investors.

The drug is being developed through an international collaboration, where Asli Shenol splits her time between the laboratory in Copenhagen and the San Diego branch of the New York-based biotech company Schrödinger.

In the epicenter of appetite
The idea for the project arose when researchers in Thue W. Schwartz’s lab discovered the receptor in the brain during another project. They already knew of it from the digestive system. The receptor is located right in the center of the brain’s appetite regulation center, specifically in the same cells where the current weight-loss drugs act by mimicking the body’s own appetite-suppressing hormones GLP-1 and amylin.

“The receptor is located in a place where a drug can easily penetrate. That’s why it’s possible to target it precisely and affect appetite regulation directly and potently,” explains Asli Shenol.

The goal of the new drug is to affect the vagus nerve, which is part of the autonomic nervous system. This nerve runs all the way from the brain to the gastrointestinal tract and is involved in regulating signals of satiety and hunger. For example, when the intestinal hormone GLP-1 signals "full" to the brain, it happens via the vagus nerve.

Normally, the receptor in the brain acts as a brake on the appetite-suppressing hormones, but by blocking the receptor, the brake is released.

This means reduced appetite and the potential for weight loss. Importantly, the drug will also enhance the effect of the current appetite-regulating agents, as their impact is usually also hindered by the receptor.

In addition, blocking the receptor is expected to calm the digestive system, which may result in fewer side effects and increased tolerance to other weight-loss medications.

Asli Shenol also hopes that the drug can help preserve muscle mass during weight loss:

“We have an idea that blocking the receptor might lead to less loss of muscle mass because it would alter the metabolic balance. But that’s one of the things we still need to investigate further,” she says.

Because the vagus nerve is involved in several diseases, including the development of Parkinson’s disease, the researchers believe that the new drug might be designed with multiple mechanisms of action.

Paul Kristjansen, Senior Scientific Director, Frontier Grants at the Lundbeck Foundation, also sees several perspectives in the project:

“Asli Shenol comes with a strong background in computational chemical modeling, tied in with Professor Thue W. Schwartz’s group, which is highly recognized for its research on gut hormones. The project contributes new insight into the function of the autonomic nervous system, including appetite regulation. This opens up exciting perspectives for more effective treatment for people living with various metabolic imbalances,” he says.

In search of the receptor’s structure
So far, the researchers have conducted pilot studies in mice and rats, examining the receptor’s normal function in healthy animals. The next step is to demonstrate the effect of blocking the receptor. However, the biggest challenge will be designing small molecules that specifically target the receptor.

But one challenge currently outweighs all the others: figuring out the structure of the receptor. The compound that binds to the receptor must fit like a 3D puzzle piece into the receptor’s structure.

“Only once we have the structure in place can we use computer modeling and analyze the receptor’s interaction with other molecules to find a compound that fits and can block it,” explains Asli Shenol.

The hunt for the receptor’s structure is taking place partly in San Diego using AI, advanced computer simulations, and modeling, and partly in Copenhagen, where Asli Shenol can test her digital results in the lab.

She is thrilled to have received the grant — especially so early in her career. Asli Shenol earned her PhD just last October.

“I’m lucky to already be working on something I’m truly passionate about, and to have the opportunity to collaborate with researchers from both industry and academia. It’s a tremendous chance for me to learn from both worlds.”

Learn more about the Lundbeck Foundation Frontier Grant: 

Frontier Grants

Frontier Grants facilitate transitions from basic research to attractive prospects for biotech investors