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Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes.

Figure 1
Scheme 1
<div class='caption-title'>Synthesis of Modified Tau Peptides 3.2a–f (Table 2) and 4.2a–g (Table 3)</div>
Andrei SA, Meijer FA, Neves JF, Brunsveld L, Landrieu I, Ottmann C, Milroy LG
OpenAccess logo ACS Chem Neurosci 9 2639-2654 (2018)
Related entries: 6fau, 6fav, 6faw, 6fbw, 6fby, 6fi4

Cited: 17 times
EuropePMC logo PMID: 29722962

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.

Reviews - 6fi5 mentioned but not cited (1)

  1. Insights into the Structural Conformations of the Tau Protein in Different Aggregation Status. Pinzi L, Bisi N, Sorbi C, Franchini S, Tonali N, Rastelli G. Molecules 28 4544 (2023)

Articles - 6fi5 mentioned but not cited (1)

  1. Inhibition of 14-3-3/Tau by Hybrid Small-Molecule Peptides Operating via Two Different Binding Modes. Andrei SA, Meijer FA, Neves JF, Brunsveld L, Landrieu I, Ottmann C, Milroy LG. ACS Chem Neurosci 9 2639-2654 (2018)


Reviews citing this publication (9)

  1. Structure and Functions of Microtubule Associated Proteins Tau and MAP2c: Similarities and Differences. Melková K, Zapletal V, Narasimhan S, Jansen S, Hritz J, Škrabana R, Zweckstetter M, Ringkjøbing Jensen M, Blackledge M, Žídek L. Biomolecules 9 E105 (2019)
  2. 14-3-3/Tau Interaction and Tau Amyloidogenesis. Chen Y, Chen X, Yao Z, Shi Y, Xiong J, Zhou J, Su Z, Huang Y. J Mol Neurosci 68 620-630 (2019)
  3. 14-3-3 Proteins: Novel Pharmacological Targets in Neurodegenerative Diseases. Pair FS, Yacoubian TA. Trends Pharmacol Sci 42 226-238 (2021)
  4. 14-3-3 Proteins are Potential Regulators of Liquid-Liquid Phase Separation. Huang X, Zheng Z, Wu Y, Gao M, Su Z, Huang Y. Cell Biochem Biophys 80 277-293 (2022)
  5. Strategies to expand peptide functionality through hybridisation with a small molecule component. Wu Y, Williams J, Calder EDD, Walport LJ. RSC Chem Biol 2 151-165 (2021)
  6. NMR Studies of Tau Protein in Tauopathies. Kitoka K, Skrabana R, Gasparik N, Hritz J, Jaudzems K. Front Mol Biosci 8 761227 (2021)
  7. Potential Therapeutic Approaches to Alzheimer's Disease By Bioinformatics, Cheminformatics And Predicted Adme-Tox Tools. Avram S, Mernea M, Limban C, Borcan F, Chifiriuc C. Curr Neuropharmacol 18 696-719 (2020)
  8. NMR Spectroscopy of supramolecular chemistry on protein surfaces. Bayer P, Matena A, Beuck C. Beilstein J Org Chem 16 2505-2522 (2020)
  9. Contemporary biophysical approaches for studying 14-3-3 protein-protein interactions. Thurairajah B, Hudson AJ, Doveston RG. Front Mol Biosci 9 1043673 (2022)

Articles citing this publication (6)

  1. A Supramolecular Stabilizer of the 14-3-3ζ/ERα Protein-Protein Interaction with a Synergistic Mode of Action. Gigante A, Sijbesma E, Sánchez-Murcia PA, Hu X, Bier D, Bäcker S, Knauer S, Gago F, Ottmann C, Schmuck C. Angew Chem Int Ed Engl 59 5284-5287 (2020)
  2. Set-up and screening of a fragment library targeting the 14-3-3 protein interface. Valenti D, Neves JF, Cantrelle FX, Hristeva S, Lentini Santo D, Obšil T, Hanoulle X, Levy LM, Tzalis D, Landrieu I, Ottmann C. Medchemcomm 10 1796-1802 (2019)
  3. Cooperative stabilisation of 14-3-3σ protein-protein interactions via covalent protein modification. Falcicchio M, Ward JA, Chothia SY, Basran J, Mohindra A, Macip S, Roversi P, Doveston RG. Chem Sci 12 12985-12992 (2021)
  4. Early increase of cerebrospinal fluid 14-3-3ζ protein in the alzheimer's disease continuum. Lu Y. Front Aging Neurosci 14 941927 (2022)
  5. A new soaking procedure for X-ray crystallographic structural determination of protein-peptide complexes. Ballone A, Lau RA, Zweipfenning FPA, Ottmann C. Acta Crystallogr F Struct Biol Commun 76 501-507 (2020)
  6. Structure-Based Optimization of Covalent, Small-Molecule Stabilizers of the 14-3-3σ/ERα Protein-Protein Interaction from Nonselective Fragments. Konstantinidou M, Visser EJ, Vandenboorn E, Chen S, Jaishankar P, Overmans M, Dutta S, Neitz RJ, Renslo AR, Ottmann C, Brunsveld L, Arkin MR. J Am Chem Soc 145 20328-20343 (2023)


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