ZwitterMPs
Membrane proteins, particularly G-protein-coupled receptors (GPCRs), represent 25-30% of current drug targets. Among them, metabotropic glutamate receptor (mGluR), a Class C and group 1 type GPCR, is emerging as an attractive therapeutic target for various neurological and psychiatric disorders such as Alzheimer’s disease, Parkinson's disease, autism spectrum disorder, schizophrenia, and neuropathic pain. Despite the availability of its complete structure, biophysical characterization and drug discovery efforts targeting mGluR have been hindered by the challenges in obtaining stable, active conformations of this receptor for in-vitro studies. To overcome this impediment, we will utilize amphiphilic zwitterionic polymers, for stabilizing mGluR. Carefully synthesizing copolymers can mimic the native lipid environment and maintain the receptor's structural and functional integrity. Zwitterionic polymers, with their unique molecular architecture featuring both anionic and cationic groups, structure surrounding water molecules, creating super-hydrophilic surfaces ideal for stabilizing membrane proteins with exposed hydrophobic domains.To evaluate this stabilization strategy, we first aim to employ the label-free bio-analytical technique of surface plasmon resonance to immobilize the mGluR-polymer complex. Secondly, we will investigate binding kinetics, affinities, and allosteric modulation of mGluR1 receptor to obtain valuable insights into protein-drug interactions. We anticipate this innovative strategy will address the existing challenges in stabilizing mGluR, offering improved stability, reduced complexity, cost-effectiveness, and higher yields over conventional methods. Moreover, it will accelerate drug screening practices targeting mGluR and other challenging membrane protein targets in the long run, thereby contributing to developing novel therapeutics for neurological and psychiatric disorders.
FYZIKALNI USTAV AV CR V.V.I (CZ); National Central University (TW)