Design and Synthesis of 6-O-Phosphorylated Heparan Sulfate Oligosaccharides to Inhibit Amyloid beta Aggregation

Dysregulation of amyloidogenic proteins and their abnormal processing and deposition in tissues cause systemic and localized amyloidosis. Formation of amyloid beta (A beta) fibrils that deposit as amyloid plaques in Alzheimer's disease (AD) brains is an earliest pathological hallmark. The polysulfated heparan sulfate (HS)/heparin (HP) is one of the non-protein components of A beta deposits that not only modulates A beta aggregation, but also acts as a receptor for A beta fibrils to mediate their cytotoxicity. Interfering with the interaction between HS/HP and A beta could be a therapeutic strategy to arrest amyloidosis. Here we have synthesized the 6-O-phosphorylated HS/HP oligosaccharides and reported their competitive effects on the inhibition of HP-mediated A beta fibril formation in vitro using a thioflavin T fluorescence assay and a tapping mode atomic force microscopy.