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Targeting pathological tau by small molecule inhibition of the poly(A):MSUT2 RNA-protein interaction.

Jeremy D. Baker,Rikki L. Uhrich,T. Strovas,Aleen D. Saxton,B. Kraemer

Published 2020 in ACS Chemical Neuroscience

ABSTRACT

Neurofibrillary tangles composed of aberrantly aggregating tau protein are a hallmark of Alzheimer's disease and related dementia disorders. Recent work has shown mammalian suppressor of tauopathy 2 (MSUT2), also named ZC3H14 (Zinc Finger CCCH-Type Containing 14), controls accumulation of pathological tau in cultured human cells and mice. Knocking out MSUT2 protects neurons from neurodegenerative tauopathy and preserves learning and memory. MSUT2 protein functions to bind poly adenosine [poly(A)] tails of messenger RNA through its C-terminal CCCH type zinc finger domains and loss of CCCH domain function suppresses tauopathy in C. elegans and mice. Thus we hypothesized, inhibiting the poly(A):MSUT2 RNA-protein interaction would ameliorate pathological tau accumulation. Here we present a high-throughput screening method for the identification of small molecules inhibiting the poly(A):MSUT2 RNA-protein interaction. We employed a fluorescent polarization assay for initial small molecule discovery with the intention to repurpose hits identified from the NIH Clinical Collection (NIHCC). Our drug repurposing development workflow included validation of hits by dose response analysis, specificity testing, orthogonal assays of activity, and cytotoxicity. Validated compounds passing through this screening funnel will be evaluated for translational effectiveness in future studies. This pre-clinical drug development pipeline identified diverse FDA approved drugs Duloxetine, Saquinavir, and Clofazimine as potential repurposing candidates for reducing pathological tau accumulation.

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