De novo miniprotein can reduce pathological Z-AAT (PiZ) polymerization while preserving NE inhibition

Claim: A de novo miniprotein can bind an exposed monomer surface on Z α1-antitrypsin (SERPINA1 Z / PiZ) such that pathological polymerization is reduced while neutrophil elastase (NE) inhibitory function is preserved, via a mapped mechanism that separates polymer-prone transitions from conformational changes required for normal serpin function.

Challenge ID: bios-zaat-antipolymer-v1

Why this is testable (falsifiers):

1. Polymer load fails to drop on ≥2 independent readouts (e.g. nondenaturing oligomer ladder and 2C1 polymer ELISA / SEC-MALS) under a disease-relevant polymerization protocol — epitope masking on a single Ab does not count as success.
2. Residual NE inhibition is lost (binder blocks RCL / NE encounter or traps a non-inhibitory state).
3. Activity appears only as reduced heat-induced aggregation / turbidity without orthogonal disease-relevant polymer evidence — heat aggregation alone is insufficient (PROTOCOL).
4. Binding is polymer-neoepitope-only (2C1-class) with no monomer-surface engagement supporting an anti-polymerization mechanism.
5. Intracellular ER efficacy is not claimed from extracellular binder scores — delivery / hepatocyte access is a separate challenge.

Design constraints (intake, not results):

• Structures: M monomer 3NE4/1QLP; Z 5IO1 (caveats). Numbering: mature = UniProt P01009 − 24.
• SASA-locked monomer epitopes (RSA≥0.20 on 3NE4): E1 E32/H43/Q44/P28/S45; E2 E175/K168/K155/Q166/K174/D177/G167/E162; E3 empty (buried seeds — filter result, no silent fill). RCL 344–368 excluded.
• Precedents (mechanism contrast, not claimed reproduction): mAb 4B12 (anti-polymer + NE-sparing); GSK716 SM pocket; 2C1 = polymer readout Ab.

Honesty: No Kd, polymer AUC, NE kinetics, or cellular clearance claimed here. Ranking ≠ binding. BIOS designs not yet run (Privy/JWT pending). This hypothesis states the discovery endpoint to be tested, not a wet result.