Finding treatments for type 2 diabetes using X-ray crystallography

Diabetes is a chronic disease and a major cause of blindness, kidney failure, heart attacks, stroke, and lower limb amputation. The drug discovery company Implexion Pharma and Lund University set out to explore new potential drug candidates for type 2 diabetes with the help of X-ray crystallography research techniques.

Diabetes occurs either when the pancreas does not produce enough insulin or when the body cannot effectively use the insulin it produces. In this case, Implexion Pharma was searching for a potential drug candidate.

The target selection for such a candidate was based on a recent finding indicating that the amino acid-derived metabolite imidazole propionate (ImP) in patients with type 2 diabetes could contribute to impaired glucose tolerance and reduced insulin signalling. The ImP is produced by the bacterial enzyme urocanate reductase (UrdA). Based on this, blocking ImP production could potentially reduce diabetic symptoms in patients.

Yet, challenges remain regarding validating and improving drug inhibitors targeting UrdA.

Revealing enzyme structures and behaviour using X-ray crystallography

Structure-based drug design utilising X-ray crystallography is ideal for developing and improving biopharmaceutical drugs. X-ray crystallography makes it possible to collect high-resolution data on small crystals and to create 3D structures.

Implexion Pharma teamed up with researchers from Lund University to perform their experiment at MAX IV in Lund, using the X-ray crystallography beamline BioMAX. They tested the structure-function of three relevant candidate compounds inhibiting the UrdA enzyme.

The data obtained at the BioMAX beamline enabled the researchers to create high-resolution structures of the three UrdA-inhibitor compounds, revealing how they inhibited the UrdA enzyme.

Towards better drugs for type 2 diabetes

The collaboration has successfully illustrated how X-ray crystallography can yield knowledge on new, better drug candidates. Based on this experiment’s findings, new molecules that can be developed into medicines are currently being synthesised.

“Collaborating with experts in X-ray crystallography and having access to state-of-the-art structure determination has fueled our hit development program, leading to potential new drugs.”

Fredrik Bäckhed, Implexion Pharma

“Structure-based drug design is a successful technique to develop and improve biopharmaceutical drugs. Using this technique to target type 2 diabetes and enable the development of novel therapeutics is an important contribution to human health”. 

Karin Lindkvist, professor of medical structural biology, Lund University