Orientation-Inspired Perspective on Molecular Inhibitor of Tau Aggregation by Curcumin Conjugated with Ruthenium(II) Complex Scaffold

Curcumin, a molecule of labile natural product, has multiplex pharmacological effects, including antioxidant, antimicrobial, and anticancer effects as well as anti-Alzheimer's disease (AD) properties. However, the drawbacks of curcumin such as poor stability and bioavailability seriously limited its application in drug development. Numerous literature studies suggested the conversion of curcumin to metal complexes and explored the clearance of beta-amyloid fibrils by curcumin conjugates. However, the research about the inhibition effect of curcumin complex on tau protein aggregation is progressing slowly, and its interactive orientation with the related proteins from the steric effect has been ignored. Inspired by the perspective on interactive orientation, we conjugated curcumin molecule on the positive-charged scaffold of Ru(II) complexes (bipyridine for Ru1, phenanthroline for Ru2) to construct an octahedral structure. After being conjugated with a ruthenium octahedral framework, curcumin exhibited a stronger ability to not only inhibit aggregation of R3, the tau peptide corresponding to the third repeat unit of the microtubule binding domain (residues 306-336 in full tau) (Ru1 with an IC50 of 0.5 mu M and Ru2 with an IC50 of less than 3 mu M) but also disaggregate R3 fibers with dose-dependence through an exothermic and dynamic process. Autodock simulation was applied to get a hairpin-docking mode in the inhibition of R3 aggregation. Herein, our results provide a rational strategy emphasizing the interactive orientation from an octahedral steric structure to design the anti-AD drugs with natural compound.