Structure-Based Selection of a Tetracycline Derivative for Advanced Biosensor Platforms Targeting Aggregated...

Parkinson's disease (PD) still lacks robust tools for early diagnosis, as current methods rely on motor symptoms that manifest after extensive neurodegeneration. Aggregated α-synuclein (α-Syn), a pathological hallmark of PD, represents a promising biomarker, yet its low abundance, polymorphic structure, and poor antibody recognition limit reliable detection. Notably, all toxic α-Syn species share a conserved cross-β motif. Building on previous findings that doxycycline binds this motif in α-Syn aggregates, we performed a structure-based selection of tetracycline derivatives to assess both binding affinity and immobilization on biosensor surfaces. Among these, 9-amino-4-dedimethylaminodoxycycline (9AD) showed improved selectivity for aggregated over monomeric α-Syn. Electrochemical and immunoassay validations confirmed its potential as a capture agent for α-Syn aggregates, supported by robust surface binding consistent with efficient immobilization. These results position 9AD as a promising biorecognition element for next-generation biosensors aimed at early PD diagnosis and pave the way for future validation in complex biological samples.