@article{479,
  keywords = {Organic Chemistry, Drug Discovery, Pharmacology, General Medicine},
  author = {László Petri and Péter Ábrányi-Balogh and Darius Vagrys and Tímea Imre and Nikolett Varró and István Mándity and Anita Rácz and Lucia Wittner and Kinga Tóth and Estilla Tóth and Tünde Juhász and Ben Davis and György Keserű},
  title = {A covalent strategy to target intrinsically disordered proteins: Discovery of novel tau aggregation inhibitors},
  abstract = {<p>Intrinsically disordered proteins (IDPs) play important roles in disease pathologies; however, their lack of defined stable 3D structures make traditional drug design strategies typically less effective against these targets. Based on promising results of targeted covalent inhibitors (TCIs) on challenging targets, we have developed a covalent design strategy targeting IDPs. As a model system we chose tau, an endogenous IDP of the central nervous system that is associated with severe neurodegenerative diseases via its aggregation. First, we mapped the tractability of available cysteines in tau and prioritized suitable warheads. Next, we introduced the selected vinylsulfone warhead to the non-covalent scaffolds of potential tau aggregation inhibitors. The designed covalent tau binders were synthesized and tested in aggregation models, and inhibited tau aggregation effectively. Our results revealed the usefulness of the covalent design strategy against therapeutically relevant IDP targets and provided promising candidates for the treatment of tauopathies.</p>
},
  year = {2022},
  journal = {European Journal of Medicinal Chemistry},
  volume = {231},
  pages = {114163},
  publisher = {Elsevier BV},
  issn = {0223-5234},
  url = {https://www.sciencedirect.com/science/article/pii/S0223523422000654},
  doi = {10.1016/j.ejmech.2022.114163},
}