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Stabilizer-Guided Inhibition of Protein-Protein Interactions.

Milroy LG, Bartel M, Henen MA, Leysen S, Adriaans JM, Brunsveld L, Landrieu I, Ottmann C
Angew Chem Int Ed Engl 54 15720-4 (2015)
Related entries: 4y3b, 4y5i, 5hf3

Cited: 28 times
EuropePMC logo PMID: 26537010

Abstract

The discovery of novel protein-protein interaction (PPI) modulators represents one of the great molecular challenges of the modern era. PPIs can be modulated by either inhibitor or stabilizer compounds, which target different though proximal regions of the protein interface. In principle, protein-stabilizer complexes can guide the design of PPI inhibitors (and vice versa). In the present work, we combine X-ray crystallographic data from both stabilizer and inhibitor co-crystal complexes of the adapter protein 14-3-3 to characterize, down to the atomic scale, inhibitors of the 14-3-3/Tau PPI, a potential drug target to treat Alzheimer's disease. The most potent compound notably inhibited the binding of phosphorylated full-length Tau to 14-3-3 according to NMR spectroscopy studies. Our work sets a precedent for the rational design of PPI inhibitors guided by PPI stabilizer-protein complexes while potentially enabling access to new synthetically tractable stabilizers of 14-3-3 and other PPIs.

Reviews - 4y32 mentioned but not cited (2)

  1. Modulators of 14-3-3 Protein-Protein Interactions. Stevers LM, Sijbesma E, Botta M, MacKintosh C, Obsil T, Landrieu I, Cau Y, Wilson AJ, Karawajczyk A, Eickhoff J, Davis J, Hann M, O'Mahony G, Doveston RG, Brunsveld L, Ottmann C. J Med Chem 61 3755-3778 (2018)
  2. 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)


Reviews citing this publication (9)

  1. Stabilization of protein-protein interactions in drug discovery. Andrei SA, Sijbesma E, Hann M, Davis J, O'Mahony G, Perry MWD, Karawajczyk A, Eickhoff J, Brunsveld L, Doveston RG, Milroy LG, Ottmann C. Expert Opin Drug Discov 12 925-940 (2017)
  2. Molecular insight into specific 14-3-3 modulators: Inhibitors and stabilisers of protein-protein interactions of 14-3-3. Hartman AM, Hirsch AKH. Eur J Med Chem 136 573-584 (2017)
  3. 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)
  4. 14-3-3: A Case Study in PPI Modulation. Ballone A, Centorrino F, Ottmann C. Molecules 23 E1386 (2018)
  5. NMR Meets Tau: Insights into Its Function and Pathology. Lippens G, Landrieu I, Smet C, Huvent I, Huvent I, Gandhi NS, Gigant B, Despres C, Qi H, Lopez J. Biomolecules 6 E28 (2016)
  6. 14-3-3 Proteins: Novel Pharmacological Targets in Neurodegenerative Diseases. Pair FS, Yacoubian TA. Trends Pharmacol Sci 42 226-238 (2021)
  7. Applications of Solution NMR in Drug Discovery. Shi L, Zhang N. Molecules 26 576 (2021)
  8. 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)
  9. NMR Spectroscopy of supramolecular chemistry on protein surfaces. Bayer P, Matena A, Beuck C. Beilstein J Org Chem 16 2505-2522 (2020)

Articles citing this publication (17)

  1. A Binary Bivalent Supramolecular Assembly Platform Based on Cucurbit[8]uril and Dimeric Adapter Protein 14-3-3. de Vink PJ, Briels JM, Schrader T, Milroy LG, Brunsveld L, Ottmann C. Angew Chem Int Ed Engl 56 8998-9002 (2017)
  2. Structure-Based Design of Non-natural Macrocyclic Peptides That Inhibit Protein-Protein Interactions. Krüger DM, Glas A, Bier D, Pospiech N, Wallraven K, Dietrich L, Ottmann C, Koch O, Hennig S, Grossmann TN. J Med Chem 60 8982-8988 (2017)
  3. Identification of Two Secondary Ligand Binding Sites in 14-3-3 Proteins Using Fragment Screening. Sijbesma E, Skora L, Leysen S, Brunsveld L, Koch U, Nussbaumer P, Jahnke W, Ottmann C. Biochemistry 56 3972-3982 (2017)
  4. Letter Biophysical and structural insight into the USP8/14-3-3 interaction. Centorrino F, Ballone A, Wolter M, Ottmann C. FEBS Lett 592 1211-1220 (2018)
  5. Fluorescence Anisotropy-Based Tethering for Discovery of Protein-Protein Interaction Stabilizers. Sijbesma E, Somsen BA, Miley GP, Leijten-van de Gevel IA, Brunsveld L, Arkin MR, Ottmann C. ACS Chem Biol 15 3143-3148 (2020)
  6. 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)
  7. 14-3-3 protein masks the nuclear localization sequence of caspase-2. Smidova A, Alblova M, Kalabova D, Psenakova K, Rosulek M, Herman P, Obsil T, Obsilova V. FEBS J 285 4196-4213 (2018)
  8. Discovery of Small-Molecule Stabilizers of 14-3-3 Protein-Protein Interactions via Dynamic Combinatorial Chemistry. Hartman AM, Elgaher WAM, Hertrich N, Andrei SA, Ottmann C, Hirsch AKH. ACS Med Chem Lett 11 1041-1046 (2020)
  9. Chimeric 14-3-3 proteins for unraveling interactions with intrinsically disordered partners. Sluchanko NN, Tugaeva KV, Greive SJ, Antson AA. Sci Rep 7 12014 (2017)
  10. Molecular Dynamics Investigations Suggest a Non-specific Recognition Strategy of 14-3-3σ Protein by Tweezer: Implication for the Inhibition Mechanism. Shi M, Xu D. Front Chem 7 237 (2019)
  11. Nuclear Magnetic Resonance Spectroscopy for the Identification of Multiple Phosphorylations of Intrinsically Disordered Proteins. Danis C, Despres C, Bessa LM, Malki I, Merzougui H, Huvent I, Qi H, Lippens G, Cantrelle FX, Schneider R, Hanoulle X, Smet-Nocca C, Landrieu I. J Vis Exp (2016)
  12. Chemical Proteomics for Target Discovery of Head-to-Tail Cyclized Mini-Proteins. Hellinger R, Thell K, Vasileva M, Muhammad T, Gunasekera S, Kümmel D, Göransson U, Becker CW, Gruber CW. Front Chem 5 73 (2017)
  13. Mono- and Bivalent 14-3-3 Inhibitors for Characterizing Supramolecular "Lysine Wrapping" of Oligoethylene Glycol (OEG) Moieties in Proteins. Yilmaz E, Bier D, Guillory X, Briels J, Ruiz-Blanco YB, Sanchez-Garcia E, Ottmann C, Kaiser M. Chemistry 24 13807-13814 (2018)
  14. A Modular Synthesis of Teraryl-Based α-Helix Mimetics, Part 5: A Complete Set of Pyridine Boronic Acid Pinacol Esters Featuring Side Chains of Proteinogenic Amino Acids. Trobe M, Schreiner T, Vareka M, Grimm S, Wölfl B, Breinbauer R. European J Org Chem 2022 e202101280 (2022)
  15. 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)
  16. A Modular Synthesis of Teraryl-Based α-Helix Mimetics, Part 3: Iodophenyltriflate Core Fragments Featuring Side Chains of Proteinogenic Amino Acids. Trobe M, Vareka M, Schreiner T, Dobrounig P, Doler C, Holzinger EB, Steinegger A, Breinbauer R. European J Org Chem 2022 e202101278 (2022)
  17. A Modular Synthesis of Teraryl-Based α-Helix Mimetics, Part 4: Core Fragments with Two Halide Leaving Groups Featuring Side Chains of Proteinogenic Amino Acids. Trobe M, Blesl J, Vareka M, Schreiner T, Breinbauer R. European J Org Chem 2022 e202101279 (2022)


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