Tryptanthrin Analogs Substoichiometrically Inhibit Seeded and Unseeded Tau4RD Aggregation.

Area of Science:

• Neuroscience
• Biochemistry
• Drug Discovery

Background:

• Microtubule-associated protein tau (MAPT) is intrinsically disordered, forming aggregates in diseases like Alzheimer's.
• Targeting tau aggregation is a key strategy for treating neurodegenerative diseases, but challenges exist due to tau's dynamic nature.
• Currently, no FDA-approved drugs specifically target tau aggregation.

Approach:

• Utilized a combination of molecular dynamics, structural analysis, and machine learning to explore tau druggability.
• Screened novel compound families, focusing on tryptanthrin and its analogs.
• Investigated structure-activity relationships (SAR) for tau aggregation inhibitors.

Key Points:

• Tryptanthrin and its analogs were identified as potent inhibitors of tau aggregation.
• The best compounds demonstrated low nanomolar potency, even at a significant molar excess of tau4RD.
• Small structural modifications in the small molecules led to substantial changes in inhibitory potency.

Conclusions:

• Tryptanthrin and its analogs represent a promising new class of tau aggregation inhibitors.
• The study demonstrates that SAR principles applicable to traditional drug development can be applied to intrinsically disordered proteins like tau.
• These findings advance the development of potential therapeutics for Alzheimer's disease and related tauopathies.