IF a fragment-based small-molecule hit series, computationally docked and iteratively elaborated against the polyanion-binding groove and Asn32 glycan-proximal surface pocket of SAP (UniProt P02743, AlphaFold model AF-P02743-F1), distal to calcium-coordination residues Asp60, Asn61, Glu138, Gln139, Asp140, Glu147, and Gln150, is administered systemically (IV or SC, dose to be determined by PK/PD modelling from lead fragment elaboration) to aged C57BL/6J mice (18–24 months, both sexes) carrying established amyloid deposits (AA or AL model),

THEN a ≥40% reduction in tissue amyloid burden (Congo red quantification and SAP-PET imaging), accompanied by measurable decrease in ex-vivo SAP–fibril co-immunoprecipitation and preserved CRP functional integrity (phosphocholine-binding ELISA), will be observed within 8 weeks of treatment,

BECAUSE the following mechanistic chain operates:

1. SAP pentamers stabilise amyloid fibrils by docking their B-face polyanion-binding groove onto the highly sulfated glycan and heparan-sulfate-like surface of fibrillar deposits; this interaction is the dominant mechanism by which fibrils evade macrophage-mediated clearance (Research Context, https://pmc.ncbi.nlm.nih.gov/articles/PMC3153594/).
2. The calcium-coordination pocket of SAP (Asp60, Asn61, Glu138, Gln139, Asp140, Glu147, Gln150) is structurally conserved with CRP; therefore, compounds targeting only this pocket would abolish both proteins' functions indiscriminately, producing pro-inflammatory liability. The polyanion groove and the Asn32 N-glycan-proximal surface are structurally unique to SAP and physically separated from the shared calcium site, making them the correct selectivity-determining pockets for fragment elaboration (Research Context, https://pmc.ncbi.nlm.nih.gov/articles/PMC3153594/).
3. Fragment-based drug discovery against AF-P02743-F1 in silico, followed by biophysical triage (SPR, STD-NMR), will identify low-MW (≤300 Da) hits binding in the Asn32-proximal cryptic pocket or the polyanion groove; these pockets are predicted by AlphaFold pLDDT surface mapping to carry high druggability scores and are accessible on the pentamer face that contacts fibril surfaces (Research Context; [SPECULATIVE — pocket druggability not yet experimentally confirmed]).
4. Lead fragment elaboration (fragment merging targeting simultaneous occupancy of the polyanion groove and the Asn32-adjacent hydrophobic patch) will produce compounds that competitively displace SAP pentamers from fibril surfaces, unmasking amyloid PAMPs for Fcγ-receptor-mediated phagocytosis and complement-directed clearance without disrupting CRP-mediated acute-phase pathogen opsonisation (Research Context, https://pmc.ncbi.nlm.nih.gov/articles/PMC3367411/).
5. Once SAP is displaced from fibrils, tissue macrophages — whose capacity to phagocytose amyloid is suppressed specifically by SAP occupancy — will resume fibril degradation, producing measurable amyloid burden reduction over 8 weeks [SPECULATI...

SENS category: GlycoSENS