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.
