The pathologic phenotype of numerous sporadic and hereditary neurodegenerative disorders is the presence of tau protein aggregates in the brain. Like many amyloidogenic proteins, the early oligomerization of tau involves conformational reorganization into stacked parallel β-sheet-like structures. The resulting fibrils are neurotoxic, and have the capacity to spread in a prion-like fashion from diseased to healthy cells causing normal tau to become misfolded. In principle, disruption of tau and similar amyloidogenic protein-protein interactions is possible through mimicry of modular aggregation-prone β-strand sequences. However, mimicry and stabilization of β-strand/sheet peptides remains a considerable challenge, where progress lags far behind α-helix and β-turn/loop mimicry. We recently established peptide backbone N-amination as a subtle yet remarkably effective strategy toward soluble and stable β-strand/sheet mimics. The conformational and non-aggregating characteristics of N-amino peptides (NAPs) are consistent across distinct models of folding in aqueous solution and the solid-state. These properties are attributed to cooperative non-covalent interactions involving the Nα-NH2 substituent. Encouraged by preliminary structural data, we developed the first solid-phase synthesis of Cα-substituted NAPs, which enables rapid peptide ‘scanning’. Unlike most existing β-strand orthotics, NAPs retain both sidechain ‘faces’ of a parent strand and are uniquely suited for capping the growth of β-sheet fibrils while maintaining the facial packing and interdigitation important for amyloid recognition. Here, we describe the design and synthesis of NAPs that block tau fibrilization and spread in a sequence-specific manner. Our N-amination strategy enables the use of tau filament structure to guide the design of its own peptidomimetic ligands. Using biophysical and cellular assays, we demonstrate the utility of a minimalist approach to target β-rich amyloids. Given that disease-associated conformational strains of tau are known to propagate <i>in vivo </i>with high fidelity, we also explore a NAP-based strategy to recognize unique structural motifs within such polymorphs. These studies provide a rational basis for the design of soluble β-strand mimics with high levels of specificity, and inform the design of other ligands for amyloid folds that are inherently difficult to target.

Tangling with tau: Beta-strand mimics targeting pathogenic protein assembly

ACS Fall 2021

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