Inhibition of 14-3-3/Tau by hybrid small-molecule peptides operating via two different binding modes

Sebastian Alexandru Andrei, Femke A. Meijer, Joao Neves, Luc Brunsveld, Isabelle Landrieu, Christian Ottmann, Lech Gustav Milroy

Research output: Contribution to journalArticleAcademicpeer-review

14 Citations (Scopus)
56 Downloads (Pure)

Abstract

Current molecular hypotheses have not yet delivered marketable treatments for Alzheimer's disease (AD), arguably due to a lack of understanding 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 structure-guided development of modified peptide inhibitors of 14-3-3/Tau. 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, and X-ray crystallography. 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 as measured by NMR spectroscopy. 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.

Original languageEnglish
Pages (from-to)2639–2654
Number of pages16
JournalACS Chemical Neuroscience
Volume9
Issue number11
DOIs
Publication statusPublished - 21 Nov 2018

Keywords

  • 14-3-3
  • drug discovery
  • inhibitors
  • peptide chemistry
  • protein-protein interactions
  • tau
  • Phosphorylation
  • Magnetic Resonance Spectroscopy
  • Humans
  • Crystallography, X-Ray
  • Drug Discovery
  • Microtubules/metabolism
  • Protein Binding
  • 14-3-3 Proteins/chemistry
  • tau Proteins/chemistry
  • Alzheimer Disease/metabolism
  • Neurofibrillary Tangles/metabolism

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