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Publication Abstract from PubMed

Current molecular hypotheses have yet to deliver marketable treatments for Alzheimer's disease (AD), arguably due to a lack of basic knowledge of AD biology, and an overreliance on conventional drug modalities. Protein-protein interactions (PPIs) are emerging drug targets, which show promise for the treatment of e.g. cancer, but are still underexploited for treating neurodegenerative diseases. 14-3-3 binding to phosphorylated Tau is a promising PPI drug target based on its reported destabilizing effect on microtubules, leading to enhanced neurofibrillary tangle formation as a potential cause of AD-related neurodegeneration. Inhibition of 14-3-3/Tau may therefore be neuroprotective. Previously, we reported the development of modified peptide inhibitors of 14-3-3/Tau using a novel structure-guided approach. Here, we report further efforts to optimize the binding mode and activity of our modified Tau peptides through a combination of chemical synthesis, biochemical assays, X-ray crystallography and NMR spectroscopy studies. Most notably, we were able to characterize two different high-affinity binding modes, both of which inhibited 14-3-3-binding to full-length PKA-phosphorylated Tau protein in vitro. Our findings, besides producing useful tool inhibitor compounds for studying 14-3-3/Tau, have enhanced our understanding of the molecular parameters for inhibiting 14-3-3/Tau, which are important milestones toward the establishment of our 14-3-3 PPI hypothesis.

Inhibition of 14-3-3/Tau by hybrid small-molecule-peptides operating via two different binding modes.,Andrei SA, Meijer F, Neves J, Brunsveld L, Landrieu I, Ottmann C, Milroy LG ACS Chem Neurosci. 2018 May 3. doi: 10.1021/acschemneuro.8b00118. PMID:29722962^[1]

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine.