A covalent strategy to target intrinsically disordered proteins: Discovery of novel tau aggregation inhibitors

Petri, László and Ábrányi-Balogh, Péter and Vagrys, Darius and Imre, Timea and Varró, Nikolett and Mándity, István and Rácz, Anita and Wittner, Lucia and Tóth, Kinga and Tóth, Estilla Zsófia and Juhász, Tünde and Davis, Ben and Keserű, György Miklós (2022) A covalent strategy to target intrinsically disordered proteins: Discovery of novel tau aggregation inhibitors. EUROPEAN JOURNAL OF MEDICINAL CHEMISTRY, 231. ISSN 0223-5234

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Abstract

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.

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