The
amyloid cascade is central for the neurodegeneration disease pathology, including Alzheimer's and Parkinson's, and remains the focus of much current research.
S100A9 protein drives the
amyloid-neuroinflammatory cascade in these diseases.
DOPA and
cyclen-based compounds were used as
amyloid modifiers and inhibitors previously, and
DOPA is also used as a precursor of
dopamine in Parkinson's treatment. Here, by using fluorescence titration experiments we showed that five selected
ligands:
DOPA-D-H-
DOPA,
DOPA-H-H-
DOPA,
DOPA-D-H,
DOPA-
cyclen, and H-E-
cyclen, bind to S100A9 with apparent Kd in the sub-micromolar range.
Ligand docking and molecular dynamic simulation showed that all compounds bind to S100A9 in more than one binding site and with different
ligand mobility and H-bonds involved in each site, which all together is consistent with the apparent binding determined in fluorescence experiments. By using
amyloid kinetic analysis, monitored by
thioflavin-T fluorescence, and AFM imaging, we found that S100A9 co-aggregation with these compounds does not hinder
amyloid formation but leads to morphological changes in the
amyloid fibrils, manifested in fibril thickening. Thicker fibrils were not observed upon fibrillation of S100A9 alone and may influence the
amyloid tissue propagation and modulate S100A9
amyloid assembly as part of the
amyloid-neuroinflammatory cascade in
neurodegenerative diseases.