Schizophrenia is a chronic and debilitating mental health disorder affecting approximately 20 million people worldwide.
Designing drugs to target glycine transporter 1 (GlyT1) could provide new treatments for schizophrenia and other psychiatric disorders. However, developing successful drug candidates has been hampered by the lack of knowledge of the GlyT1 structure.
To reveal the 3D structure of GlyT1 and gain insights into new strategies for drug design, researchers from F. Hoffmann-La Roche (known as Roche), Linkster Therapeutics, and the Danish Research Institute of Translational Neuroscience (DANDRITE) at Aarhus University, which is part of the Nordic EMBL Partnership for Molecular Medicine, collaborated with EMBL Hamburg.
Roche had been investing in drug discovery projects to develop small-molecule inhibitors for GlyT1 for over a decade. One of its most promising drug candidates, bitopertin, had reached phase III clinical trials but failed to show any efficacy compared to placebo.
One of Roche’s lead researchers, Roger Dawson (now founder and Chief Executive Officer of Linkster Therapeutics), wanted to understand why the drug had failed, as this could provide new insights to design better drugs.
Dawson initially teamed up with Poul Nissen and postdoc Azadeh Shahsavar from DANDRITE. The Nissen Group set out to resolve the structure of GlyT1 in combination with bitopertin using X-ray crystallography, a powerful technique that provides detailed 3D models of proteins to gain insights into their structure and function.
When standard methods to resolve the structure of GlyT1 failed, the research team brought in EMBL's expertise in developing advanced methodologies. The EMBL Interdisciplinary Postdoctoral (EIPOD) programme was an important enabler of the collaboration; EIPOD supports postdocs to work on research projects involving academic and industry partners in collaboration with scientists at EMBL. "The EIPOD programme helped open up and accelerate discussions with Roche now that we were putting the project in a cutting-edge collaboration with EMBL," commented Nissen, Director of DANDRITE and senior researcher on the study. Shahsavar was able to collect the data for the study during her time as a postdoc in the EIPOD programme, during which she worked at EMBL Hamburg, DANDRITE, and Roche.
At EMBL Hamburg, Shahsavar worked in the Schneider Group, which developed the Serial Synchrotron Crystallography approach that allowed her to collect data from hundreds of microcrystals using EMBL Hamburg's state-of-the-art P14 beamline. The Schneider Group then developed software to combine data from microcrystals to reveal the full picture of GlyT1 at high resolution. "The game changer was when EMBL joined and brought the advanced methodology and softwareto enable this project to [reach] the end stage," said Dawson.
Thomas Schneider, Joint Head of EMBL Research Infrastructures, commented: "For challenging projects like this, we are happy to put the methodological expertise of our staff to work and to make full use of the technological capabilities of our beamlines and sample preparation facilities." Nissen agreed: "EMBL has proved time and time again they can really drive developments in imaging and bioinformatics."
Azadeh Shahsavar et al. Structural insights into the inhibition of glycine reuptake. Nature, published on 3 March 2021. DOI: 10.1038/s41586-021-03274-z
The structure of GlyT1 was published in the leading scientific journal Nature. The study highlights the importance of both scientific excellence and the availability of cutting-edge infrastructure, advanced methodology, and software for progressing research – all of which are provided by EMBL Hamburg.
Findings from the study provided insights into why the drug candidate bitopertin failed to inhibit GlyT1: “This structure provides a blueprint for developing new inhibitors of GlyT1, be they organic molecules or antibodies,” explained Dawson. The study also uncovered a binding site on GlyT1 that inhibits its function; this knowledge can be used to develop drugs targeting GlyT1 and other membrane transport proteins.
DANDRITE continues to benefit from being part of the Nordic EMBL Partnership. As Nissen explained, “We [DANDRITE] are more interesting to the outside world and to industry being so tightly connected to EMBL through a partnership. The EMBL brand has opened opportunities for many other grant applications and collaborations.” Shahsavar added: “As an external user, I keep thinking of ways to keep my link to EMBL. It’s not just the infrastructure, it’s the science-focused mentality. I haven’t seen that in many places.”
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