Ligand polarizability contributes to tau fibril binding affinity

Area of Science:

• Neuroscience
• Radiochemistry
• Drug Discovery

Background:

• Whole brain imaging of tau-bearing neurofibrillary lesions can improve Alzheimer's disease (AD) diagnosis and staging.
• High-throughput screening has identified diverse compounds with high affinity for tau aggregates, but common affinity-driving features remain undetermined.

Purpose of the Study:

• To identify common features driving high affinity among structurally diverse tau-binding ligands.
• To assess the predictive utility of synthetic tau filaments for ligand development.
• To optimize ligand discovery efforts for tau aggregates in Alzheimer's disease.

Main Methods:

• Analogs of phenothiazine, triarylmethine, benzothiazole, and oxindole derivatives were synthesized and tested.
• Binding affinity was assessed by displacement of fluorescent thioflavin dyes from recombinant tau filaments and authentic paired helical filaments (PHFs) from AD tissue.
• Structure-activity relationships were analyzed, focusing on parameters like compound polarizability.

Main Results:

• A strong correlation was observed between the binding affinity rank order for synthetic and authentic tau filaments, validating synthetic filaments for ligand development.
• Within scaffold families, binding affinity correlated positively with compound polarizability, suggesting the role of dispersion forces.
• Structurally diverse tau-binding ligands share polarizability as an important common feature.

Conclusions:

• Polarizability is a critical parameter for maximizing the affinity of structurally diverse ligands for tau aggregates.
• Integrating polarizability assessment into ligand discovery can enhance the development of effective tau-binding agents for Alzheimer's disease imaging.
• Synthetic tau filaments serve as a reliable model for developing ligands targeting neurofibrillary lesions.