Structure-based development of new cyclic compounds targeting PSD-95 PDZ3 domain

Area of Science:

• Neuroscience
• Molecular Biology
• Drug Discovery

Background:

• Aberrant Brain-Derived Neurotrophic Factor (BDNF) signaling is implicated in depression and neurological disorders like Angelman syndrome.
• The TrkB/PSD-95 signaling pathway is a potential therapeutic target.
• Previous work identified peptidomimetic inhibitors of the TrkB/PSD-95 nexus.

Approach:

• Developed novel peptidomimetic compounds by fusing SynGAP-derived peptides to a prototype inhibitor (CN2097).
• Utilized structure-based design for bivalent binding to the PSD-95 PDZ3 domain and adjacent αC helix.
• Conducted structure-activity relationship (SAR) studies to enhance specificity and proteolysis resistance.

Key Points:

• The new compounds exhibit up to 7-fold increased binding affinity compared to the prototype CN2097.
• Bivalent binding enhances interaction with the target PSD-95 PDZ3 domain and αC helix.
• Compounds designed for improved specificity and potential for increased stability against degradation.

Conclusions:

• Novel bivalent peptidomimetics demonstrate significantly improved affinity for the PSD-95 PDZ3 target.
• These compounds represent a promising advancement in targeting the TrkB/PSD-95 pathway for neurological disorders.
• Further development could lead to more effective therapeutics for conditions linked to BDNF signaling.