Rajewski, Benjamin: Proteomimetic models and inhibitors of disease-associated tau assembly

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Rajewski, Benjamin: Proteomimetic models and inhibitors of disease-associated tau assembly


Title: Models and Inhibitors of Disease-Associated Tau Assembly

Rajewski, Benjamin, University of Notre Dame; Kamlesh Makwana, University of Notre Dame; Isaac Angera, University of Notre Dame; Arnaldo Serrano, University of Notre Dame; Grace Hallinan, Indiana University School of Medicine; Ruben Vidal, Indiana University School of Medicine; Bernardino Ghetti, Indiana University School of Medicine; Juan R. Del Valle, University of Notre Dame


Background/Significance/Rationale: The formation and spread of neurofibrillary tangles comprised of aggregated tau protein is central to the progression of Alzheimer’s Disease and other tauopathies. Recent cryo-EM data suggest that fibrillar tau adopts unique folds in various diseases, resulting in the aggregation-prone VQIVYK sequence (PHF6) engaging in a cross-β interaction with an opposing hexapeptide b-strand depending on the tauopathy. Aggregation model systems based on truncated tau variants do not account for these interactions, and often rely on cofactors which may not be biologically relevant.

Methods: In this work, macrocyclic epitope mimics of conformational strains of tau, dubbed ‘β-bracelets,’ were prepared by solid-phase synthesis followed Cys bis-alkylation. Our designs incorporate the PHF6 sequence and unique cross-β interacting strands from specific tau conformations. Self-aggregation propensity was assayed via thioflavin T fluorescence (ThT) and transmission electron microscopy (TEM). Backbone N-amination chemistry yielded a series of β-bracelet inhibitors that were tested against tau aggregation in ThT, TEM, and cell-based assays.

Results/Findings: β-Bracelets aggregate rapidly without the need for additional cofactors and form fibrillar structures with unique morphologies when visualized by TEM. Furthermore, backbone N-amination of parent β-bracelets affords macrocyclic N-amino peptide (NAP) inhibitors of tau aggregation. These NAPs block the fibrilization of recombinant tau P301L in vitro as well as the seeding of endogenous tau in a cell-based reporter assay.

Conclusions/Discussion: Incorporation of tau cross-β modules into a small peptide macrocycle yielded minimally designed molecules capable of aggregating in an amyloid-like fashion. Bracelet backbone-N amination blocked β-bracelet self-aggregation and potently inhibited aggregation of P301L tau. This proteomimetic strategy thus enables the rational design of ligands that may be able to discriminate between closely related amyloid folds.

Translational/Human Health Impact: The development of synthetic mimics of pathogenic tau folds could provide valuable insight into the role of cross-β interactions in fibrilization. Such compounds would also enable the development of assays to identify selective chemical probes and serve as a template for the design of potent inhibitors of tau aggregation.


|2022-08-31T17:24:39-04:00August 23rd, 2022|2022 Annual Meeting Presentations|Comments Off on Rajewski, Benjamin: Proteomimetic models and inhibitors of disease-associated tau assembly

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James Dudley

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