Novel glycosaminoglycan precursors as anti-amyloid agents part II

In vivo amyloids consist of two classes of constituents. The first is the disease defining protein, e.g., Aβ in Alzheimer’s disease. The second is a set of common structural components that usually are the building blocks of basement membrane (BM), a tissue structure that serves as a scaffold onto which cells normally adhere. In vitro binding interactions between one of these BM components and amyloidogenic proteins rapidly change the conformation of the amyloidogenic protein into amyloid fibrils. The offending BM component is a heparan sulfate (HS) proteoglycan (HSPG), part of which is protein and the remainder a specific linear polysaccharide, which is the portion responsible for binding, and imparting the typical amyloid structure, to the amyloid precursor protein/peptide. Our past work has demonstrated that agents that inhibit the binding between HS and the amyloid precursor are effective anti-amyloid compounds both in vitro and in vivo. The present work is concerned with the design and synthesis of modified sugar precursors of HS, which, when incorporated into the polysaccharide, will alter its structure so that it loses its amyloid precursor protein/peptide-binding and fibril-inducing properties.