Preliminary evaluation of a modular tau-targeting peptide fused to a p62/SQSTM1 LC3-interacting motif

Tau reduction through targeted degradation has motivated several molecular strategies, including small-molecule degraders and peptide-based approaches. We designed a 47-amino-acid bifunctional peptide (GS-47) comprising a computationally selected tau-targeting segment, a glycine-serine linker, and the p62/SQSTM1-derived LC3-interacting region sequence DDDWTHLSS. The tau-targeting module was generated using RFdiffusion and ProteinMPNN against the tau filament structure PDB 8TTL and evaluated using predicted structural confidence metrics. GS-47 was tested in SH-SY5Y cells using a 24-hour endpoint Human MAPTau sandwich ELISA, with QC-01-175 as a PROTAC comparator and YA041 as an antibody reference. At the 1:10 ELISA dilution, GS-47 and QC-01-175 produced similar A450 values (0.227 and 0.231, respectively), both within the detectable standard range. Vehicle controls failed quality control, preventing normalization and formal quantitative comparison. We present this as a preliminary design-and-assay observation that motivates repeat experiments with normalization controls, orthogonal tau measurements, and mechanism-specific perturbations.