What structural features make pathological tau epitopes druggable compared to physiological tau conformations?

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Composite

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Novelty

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Mechanistic

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Druggability

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Priority

85%

Importance

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Tractability

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Market price

50%

Description

The debate highlighted the need for druggability assessment but never examined which structural changes in pathological tau create targetable binding sites. This knowledge gap prevents rational drug design approaches.

Source: Debate session sess_SDA-2026-04-10-SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd (Analysis: SDA-2026-04-09-gap-debate-20260409-201742-1e8eb3bd)

Resolution criteria

Gap closes when: (1) Cryo-EM or X-ray crystallography resolves the structure of pathological tau filaments (Alzheimer or Pick conformation) at <= 3.5 Angstrom resolution and identifies >= 3 cryptic pockets absent in monomeric tau; and (2) in silico docking or fragment screening identifies small molecules with Kd < 10 uM that preferentially bind pathological over monomeric tau (>= 10-fold selectivity); and (3) at least one compound reduces tau seeding in a cell-based FRET assay by >= 40% at non-toxic concentrations. Deliverable: structural data deposited in PDB and validated hit compounds with selectivity profile.

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