Tau is a neuronal microtubule associated protein (MAP), promoteing the assembly and bundling of microtubules and suppressing microtubule (MT) dynamics. Abnormal functioning of tau is implicated in several neuronal disorders such as Alzheimer's disease wherein tau forms insoluble aggregates and causes neurotoxicity. As an intrinsically disordered protein, tau competes with other MAPs to regulate microtubule function tightly and make it more refined. More and more results showed that tau may produce a transient helical conformation to interact with microtubule. Based on cryo-EM data of tau MTBR-MT complex, we designed several tau-derived hydrogen bond surrogate (HBS) peptides based on peptide sequence starting from SKIGS involved in tau-MT interaction. The preparation of end product was enabled by optimized solid-phase and liquid-phase synthesis, starting from the classical SPPS of peptide modified with <i>N</i>-allyl group to the amino acid residues at proper positions, and then the modified peptides were cleaved from the resin which were subjected to ring closure metathesis reaction in liquid phase. These compounds were analyzed by CD spectra for their conformations and evaluated in bioassays including MT polymerization assay.

Design and synthesis of tau-derived peptides to modulate microtubule function

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ACS Fall 2022

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