pH-Inverted Histidine-Rich Nanochelants for Trapping Furin-Processed Polycationic Nanotoxins: A Quantum-Classical Platform for Dual Heavy-Metal Detoxification and Broad-Spectrum Countermeasures

Furin cleaves polybasic sites in endosomes and the secretory pathway, releasing linear (>3 net positive charges) and concentric (metal-coordinating) nanotoxins that drive metabolic disease, cytokine storms, neurodegeneration, autoimmunity, cancer immune evasion, and infection. We introduce 5H-EAF, an erythritol-capped linear penta-histidine nanochelant (MW ≈ 880 Da) that activates to +4–5 net charge at endosomal pH 5.5–6.5, trapping these species via electrostatic clamping and coordination, then deprotonates and releases harmlessly at neutral pH. DFT (B3LYP-D3/def2-TZVP, explicit solvation) yields Pb²⁺ ΔG = –11 to –16 kcal/mol (low pH) → –3 to –6 kcal/mol (neutral); SARS-CoV-2 PRRAR⁺ motif clamping ΔG ≈ –8 to –13 kcal/mol; and anthrax PA63 pore blockade analogous to validated cationic blockers (Kd nM–µM, planar-bilayer literature) supported by all-atom MD simulations (MM-PBSA ΔG = −28.7 kcal/mol at pH 5.5). The platform speaks furin’s native pH/Ca²⁺/charge language without global inhibition. It unifies GLP-1 optimization, cytokine control, α-syn/amyloid management, Pb neuroprotection, and biodefense against furin-dependent pathogens (anthrax, Ebola, H5N1, SARS-CoV-2, Dengue).