Amyloid-associated hypersulfated heparan sulfate proteoglycan complex

The target consists of the pathological complex formed by extracellular amyloid fibrils and the hypersulfated heparan sulfate proteoglycans (HSPGs) that co-deposit with them. In various forms of amyloidosis, such as AL, ATTR, and AA, as well as in Alzheimer's disease, these HSPGs (notably perlecan) undergo a unique hypersulfation process that is absent in healthy tissues [3, 18, 21]. This hypersulfated state creates a high negative charge density that facilitates the binding, stabilization, and accelerated aggregation of misfolded protein fibrils [5, 17]. By protecting fibrils from proteolytic degradation and promoting their growth, the complex plays a central role in the progression of organ-damaging amyloid deposits [19, 22]. Therapeutic strategies targeting this complex include small molecules like eprodisate, which competitively inhibit the HS-fibril interaction, and peptide-based opsonins like AT-02, which bind the complex to recruit macrophages for phagocytic clearance [1, 8, 9]. Because hypersulfated HS is a ubiquitous component of amyloid deposits regardless of the precursor protein, it serves as a pan-amyloid target for both diagnostic imaging and broad-spectrum therapy [6, 10, 20]. This approach directly addresses the existing pathological deposits responsible for organ dysfunction, offering a potential advantage over therapies that only target precursor protein production [13, 18].

Other names

Extracellular amyloid fibrils and deposits and associated hypersulfated heparan sulfate proteoglycansAmyloid-associated glycosaminoglycansHypersulfated heparan sulfatePan-amyloid targetAmyloid-HSPG complex

Competitive inhibition of glycosaminoglycan-fibril binding and opsonization of amyloid deposits for macrophage-mediated phagocytic clearance.