. Structure-based inhibitors of tau aggregation. Nature Chemistry. November 20, 2017.

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  1. Aggregated tau protein plays a significant role in a variety of neurological disorders, including Alzheimer’s disease. The development of specific compounds to inhibit tau aggregation can aid the development of therapies and might help to elucidate the pathologic mechanisms of the various tauopathies. The sequence segments VQIVYK and VQIINK are well known to drive tau aggregation, and peptides were already developed to block tau aggregation by binding to the VQIVYK segment, which is central to the core of tau fibrils extracted from AD brain tissue (Fitzpatrick et al., 2017; Sievers et al., 2011; Dammers et al., 2016). 

    In this recent article, Seidler et al. described the structure of VQIINK containing fibrils, resolved by micro-electron diffraction (microED). The segment formed a face-to-face Type 1 homosteric zipper, like VQIVYK (Sievers et al., 2011), but with a stronger interface. The determination of the VQIINK fibril structure is a great success and the result of much hard work (for a decade, efforts of the group were unsuccessful), and was made possible only by the invention of microED. The authors used the structure to design peptide inhibitors of tau aggregation, which inhibited aggregation of full-length tau but also the ability of exogenous full-length tau fibrils to seed intracellular tau in HEK293 biosensor cells into amyloid fibers. These results were compared to the performance of a VQIVYK binding peptide D-TLKIVW, which was also designed to block tau aggregation (Sievers et al., 2011). The latter peptide was not able to block full-length tau aggregation, nor could it inhibit tau seeding in the HEK293 biosensor model.

    In addition, the authors developed tau K18 isoforms that possessed two VQIINK or two VQIVYK motifs and found that the variant with two VQIINK motifs fibrillized more rapidly, whereas the other variant formed more tau oligomers (the more toxic species?). The authors concluded that the VQIINK fragment was the more powerful driver of tau aggregation and a superior target for the development of tau aggregation inhibitors.

    Which of the motifs is the superior target for tau aggregation inhibitor development is to be proven in the future. Recently, we have developed D-enantiomeric peptides, which were selected to bind to VQIVYK fibrils. These peptides, in contrast to D-TLKIVW, were able to inhibit full-length tau fibrillization (Dammers et al., 2016). Their potential to inhibit the ability of exogenous full-length tau fibrils to seed intracellular tau is not tested yet, but might interesting to evaluate.

    References:

    . Cryo-EM structures of tau filaments from Alzheimer's disease. Nature. 2017 Jul 13;547(7662):185-190. Epub 2017 Jul 5 PubMed.

    . Structure-based design of non-natural amino-acid inhibitors of amyloid fibril formation. Nature. 2011 Jul 7;475(7354):96-100. PubMed.

    . Selection and Characterization of Tau Binding ᴅ-Enantiomeric Peptides with Potential for Therapy of Alzheimer Disease. PLoS One. 2016;11(12):e0167432. Epub 2016 Dec 22 PubMed.

    View all comments by Susanne Aileen Funke

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  1. From New Tau Structure, Bona Fide Aggregation Inhibitors?