Which specific post-translational modifications create druggable epitopes unique to pathological tau?

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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

90%

Importance

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Tractability

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Market price

50%

Description

The debate was structured around this question but no literature was provided to address it. Identifying these modifications is critical for developing selective therapeutics that target diseased tau without affecting normal tau function.

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

Resolved when a structure-activity relationship campaign targeting >=3 candidate pathological tau PTM sites (pS202, pT205, pS396, or acetyl-K280) identifies a compound or peptide with: (a) Kd < 100 nM for pathological tau epitope (SPR or ITC), (b) >=50-fold selectivity over normal tau (competitive ELISA with AT8- vs Tau5-immunoprecipitated protein), and © cell permeability (Papp A->B >= 10e-6 cm/s, Caco-2 or MDCK assay). Deliverable: compound structure and assay data deposited in ChEMBL; SciDEX KG druggable-tau-PTM subgraph created with >=3 characterised epitope nodes.

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