Discovery of a tau-aggregate clearing compound that covalently targets P4HB

The improper folding and aggregation of tau are linked to several neurodegenerative diseases affecting millions worldwide. However, the pathogenesis of tauopathies remains poorly understood, resulting in limited effective treatments. Here, we employ an integrated chemoproteomic phenotypic strategy to identify druggable targets and corresponding chemical probes for the treatment of tauopathies. We identified and optimized an indole-amine compound that potently and extensively clears tau aggregates in two human tauopathy models. Mechanistic and chemoproteomic studies implicate protein disulfide isomerase 1 (P4HB) as the primary target, forming covalent adducts upon metabolic activation. Knockdown of P4HB reduced tau aggregates in three tauopathy models, including an ex vivo murine neuron preclinical model. Functional characterization revealed the compound induces mild endoplasmic reticulum (ER)-stress responses as assessed by RNA sequencing and whole proteomic profiling. Our findings highlight P4HB as a potential therapeutic target for treatment of tauopathies.