Researchers at the École Polytechnique Fédérale de Lausanne (EPFL) and AstraZeneca have developed a novel formulation that could change diabetes management. Using protein crystallization techniques, they created a way to map the atomic-level structure of GLP-1 receptor (GLP-1R) agonists. Such drugs, which are now critical to the management of diabetes and the treatment of obesity, are currently injected on a daily or weekly basis. The introduction of effective oral alternatives would significantly improve patient comfort and adherence to treatment.
The research team’s innovative approach seeks to address one of the major challenges in drug development: solubility. Scientists employ cutting-edge solid-state nuclear magnetic resonance (NMR) technology to unlock the molecular structures of GLP-1R agonists. They zoom in on these structures in their formless, jelly-like state. A new study published in the Journal of the American Chemical Society provides a window into these important interactions. It further points to the preferred conformations that stabilize these drugs.
Understanding GLP-1R Agonists
The GLP-1R agonists are taking a central role in the treatment of diabetes and obesity. They’re effective because they mimic the incretin hormone GLP-1, which helps control blood sugar levels and appetite. Today, the only way for patients to get these medications is via injection—the experience of which can be painful and result in reduced patient compliance with treatment regimens.
Today, the need for oral alternatives is more important than ever. If practical oral formulations can be achieved, it would represent a much more convenient, pleasant benefit for patients. This amendment would be a huge step towards bringing more compliance to people controlling chronic illnesses such as diabetes.
The Challenge of Solubility
One of the biggest challenges in creating oral drugs, especially for large molecules, is solubility. Numerous currently available drugs, such as GLP-1R agonists, poorly dissolve within the gastrointestinal tract, restricting their therapeutic efficacy after oral administration. Addressing this issue is crucial for creating viable oral formulations that can deliver therapeutic benefits without the need for injections.
The scientists at EPFL and AstraZeneca are meeting this challenge head-on by precisely mapping the atomic structure of these drugs. Their research informs their understanding of how molecular composition relates to the solubility and stability of bottle compositions. Such a detailed understanding lays the groundwork for the development of oral GLP-1R agonists.
Innovative Methodology
This study adds something new — a unique approach to the entire modeling process. It employs solid-state NMR to study the response of atomic nuclei in GLP1R agonists to external magnetic fields. The team ran the equivalent of more than nine million possible molecular environments through simulations on the most advanced supercomputers. This significant computational simulation effort allowed them to obtain high-resolution information about the drug’s binding structure.
To better inform their analysis, the researchers used a new machine learning tool developed by C40 named ShiftML2. This tool has been used to accurately predict the corresponding chemical shifts based on the various distinct molecular environments being simulated. With the use of ShiftML2, this atomic structure of the drug could be represented more accurately.
Using this approach, the team was able to zoom into one experimental GLP-1R agonist developed by AstraZeneca. Their findings revealed chemical shift distributions for 17 carbon and 16 hydrogen atoms within the molecule. This safety data may be important in determining shelf-life and potency of the drug.
Implications for Future Research
The study’s results indicate that the amorphous form of the GLP-1R agonist possesses a unique structure that facilitates the identification of hydrogen-bonding interactions and preferred conformations. These specific interactions play a critical role in stabilizing the amorphous form, which is a key step in designing superior oral formulations.
As scientists work to develop a deeper understanding of this field, the potential for new diabetes treatments would be significant. Developing stable oral substitutes for existing injection-based therapies can greatly improve patient satisfaction. We hope that this innovation opens the door to demonstrating improved health outcomes as well.
