Abstract / Summary
Abstract Selective control of pathogenic protein self-assembly remains a major challenge for intrinsically disordered amyloid-forming proteins such as Tau. Here we show that nanobodies originally raised against the chaperone S100B unexpectedly cross-react with Tau as potential pathway-selective modulators of Tau self-assembly. Guided by overlap between Tau- and nanobody-binding surfaces on S100B, we show that selected nanobodies bind Tau monomers and fibrillar seeds inhibiting Tau aggregation in a concentration-dependent manner. Kinetic analysis supports distinct inhibitory profiles, with global fitting consistent with preferential targeting of primary or secondary nucleation pathways, suggesting a differential modulation of the formation of nucleation-derived species. Notably, one nanobody strongly suppresses surface-catalyzed secondary nucleation, markedly reduces the simulated burden of these species and inhibits Tau seeding in a FRET biosensor cell model. Together, these results identify chaperone-inspired nanobodies as molecular binders whose effects are consistent with pathway-selective control of Tau self-assembly and support the use of endogenous anti-aggregation proteins as templates for discovering binders against aggregation-prone disordered targets.