What structural differences between physiological and pathological tau enable selective drug targeting?

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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 framework assumed such differences exist but provided no evidence characterizing them. Understanding these structural distinctions is essential for designing drugs that avoid disrupting normal tau biology.

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) HDX-MS or cryo-EM comparison of physiological tau, tau in pre-fibrillar oligomers, and tau in mature filaments identifies >= 5 regions with >= 50% difference in deuterium uptake or B-factor; and (2) at least one region corresponds to a druggable pocket by DoGSite or fpocket analysis (volume > 300 cubic Angstrom, hydrophobicity score > 0.5); and (3) a selective binder (peptide, small molecule, or nanobody) to that region demonstrates <= 5% cytotoxicity at the active concentration in primary neurons. Deliverable: comparative structural dataset with pocket analysis and selectivity validation.

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