Neurodegenerative diseases pose an increasing health risk and represent one of the greatest therapeutic challenges of our time. There is currently no cure for most of them. GlyT1 and GlyT2 glycine transporters control the transport of the neurotransmitter glycine across neuronal membranes in the brain and are promising therapeutic targets for several neurological disorders.
Despite extensive research, inhibitors of GlyT1 and GlyT2 have failed in preclinical and clinical studies due to low efficacy or significant side effects. A successful drug that modulates these neurotransmitter systems has yet to be developed.
In this project, our aim is to overcome the limitations of classical GlyT inhibitors by exploiting an endogenous allosteric regulatory mechanism of glycine transport. Using synthetic single-domain antibodies (sybodies) selected specifically for the inhibited state of the transporters, we will be able to lock them at a surface-exposed site distinct from the glycine-binding site and prolong glycine exposure. Combining cryo electron microscopy (cryo EM) with molecular biophysics studies will enable us to uncover the molecular mechanisms and structural determinants of allosteric inhibition.
This research project will lay the groundwork for identifying new therapeutic agents and novel strategies for effectively targeting glycine transporters. The methodological innovations developed will also be applicable to other protein targets.
Figure 1. Glycine transporters-mediated regulation of glycine neurotransmission at excitatory and inhibitory synapses. Excitatory glutamatergic synapse (left) and inhibitory glycinergic synapse (right) are depicted. GlyT1 (cyan), and GlyT2 (purple), the main regulators of glycine concentrations and dynamics of glycine neurotransmission in the synapse, are depicted. Extracellular and intracellular glycine concentrations created by GlyT1 and GlyT2 in different locations of the synapse are shown.
For further information about this HALRIC pilot project, please contact:
Azadeh Shahsavar
University of Copenhagen
ash@sund.ku.dk
