Potent PDZ-Domain PICK1 Inhibitors that Modulate Amyloid Beta-Mediated Synaptic Dysfunction

Area of Science:

• Neuroscience
• Molecular Biology
• Pharmacology

Background:

• Protein interacting with C kinase (PICK1) is a scaffolding protein crucial for neuronal function.
• PICK1 regulates AMPA receptor trafficking via interaction with the GluA2 subunit, impacting synaptic plasticity, learning, and memory.
• Developing selective PICK1 inhibitors is essential for therapeutic exploration in neurological diseases.

Purpose of the Study:

• To discover potent and selective small molecule inhibitors of the PICK1 PDZ domain.
• To investigate the therapeutic potential of targeting the PICK1-GluA2 interaction for neurological disorders.

Main Methods:

• Structure-based drug design strategy was employed to identify PICK1 inhibitors.
• Inhibitor efficacy was assessed by measuring stabilization of surface GluA2.
• Functional assays included evaluating Aβ-induced intracellular calcium changes in neurons and blocking long-term depression in brain slices.

Main Results:

• Novel small molecule inhibitors targeting the PICK1 PDZ domain were successfully discovered.
• The identified inhibitors demonstrated the ability to stabilize surface GluA2.
• Inhibitors reduced Aβ-induced calcium influx in neurons and inhibited long-term depression in brain slices.

Conclusions:

• Potent and selective PICK1-GluA2 inhibitors can be identified using structure-based drug design.
• These inhibitors show promise in modulating neuronal function relevant to neurodegenerative diseases.
• The findings support the therapeutic potential of targeting the PICK1-GluA2 interaction for treating neurological disorders.