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An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB-Utilizing a Reversible Covalent Tethering Approach.

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Wolter M, Valenti D, Cossar PJ, Hristeva S, Levy LM, Genski T, Hoffmann T, Brunsveld L, Tzalis D, Ottmann C
OpenAccess logo J Med Chem 64 8423-8436 (2021)

Cited: 10 times
EuropePMC logo PMID: 34076416

Abstract

Protein-protein modulation has emerged as a proven approach to drug discovery. While significant progress has been gained in developing protein-protein interaction (PPI) inhibitors, the orthogonal approach of PPI stabilization lacks established methodologies for drug design. Here, we report the systematic ″bottom-up″ development of a reversible covalent PPI stabilizer. An imine bond was employed to anchor the stabilizer at the interface of the 14-3-3/p65 complex, leading to a molecular glue that elicited an 81-fold increase in complex stabilization. Utilizing protein crystallography and biophysical assays, we deconvoluted how chemical properties of a stabilizer translate to structural changes in the ternary 14-3-3/p65/molecular glue complex. Furthermore, we explore how this leads to high cooperativity and increased stability of the complex.

Articles - 7o5f mentioned but not cited (1)

  1. An Exploration of Chemical Properties Required for Cooperative Stabilization of the 14-3-3 Interaction with NF-κB-Utilizing a Reversible Covalent Tethering Approach. Wolter M, Valenti D, Cossar PJ, Hristeva S, Levy LM, Genski T, Hoffmann T, Brunsveld L, Tzalis D, Ottmann C. J Med Chem 64 8423-8436 (2021)


Reviews citing this publication (3)

  1. Molecular glues modulate protein functions by inducing protein aggregation: A promising therapeutic strategy of small molecules for disease treatment. Wu H, Yao H, He C, Jia Y, Zhu Z, Xu S, Li D, Xu J. Acta Pharm Sin B 12 3548-3566 (2022)
  2. Protein-protein interactions: developing small-molecule inhibitors/stabilizers through covalent strategies. Lucero B, Francisco KR, Liu LJ, Caffrey CR, Ballatore C. Trends Pharmacol Sci 44 474-488 (2023)
  3. 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. miR-203, fine-tunning neuroinflammation by juggling different components of NF-κB signaling. Li S, Li L, Li J, Liang X, Song C, Zou Y. J Neuroinflammation 19 84 (2022)
  2. Nedd4-2 binding to 14-3-3 modulates the accessibility of its catalytic site and WW domains. Joshi R, Pohl P, Strachotova D, Herman P, Obsil T, Obsilova V. Biophys J 121 1299-1311 (2022)
  3. Reversible Dual-Covalent Molecular Locking of the 14-3-3/ERRγ Protein-Protein Interaction as a Molecular Glue Drug Discovery Approach. Somsen BA, Schellekens RJC, Verhoef CJA, Arkin MR, Ottmann C, Cossar PJ, Brunsveld L. J Am Chem Soc 145 6741-6752 (2023)
  4. A simple method for developing lysine targeted covalent protein reagents. Gabizon R, Tivon B, Reddi RN, van den Oetelaar MCM, Amartely H, Cossar PJ, Ottmann C, London N. Nat Commun 14 7933 (2023)
  5. Towards identification of protein-protein interaction stabilizers via inhibitory peptide-fragment hybrids using templated fragment ligation. Srdanović S, Hegedüs Z, Warriner SL, Wilson AJ. RSC Chem Biol 3 546-550 (2022)
  6. Tracking the mechanism of covalent molecular glue stabilization using native mass spectrometry. Verhoef CJA, Kay DF, van Dijck L, Doveston RG, Brunsveld L, Leney AC, Cossar PJ. Chem Sci 14 6756-6762 (2023)


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