Amyloid fibrils and associated hypersulfated heparan sulfate glycans

Amyloid fibrils and associated hypersulfated heparan sulfate glycans represent a complex pathological target found in all forms of systemic and localized amyloidosis [2, 4]. Amyloid deposits are not merely protein aggregates but are organized matrices containing misfolded protein fibrils (such as light chain or transthyretin) and accessory molecules, most notably hypersulfated heparan sulfate proteoglycans (HSPGs) [5, 11]. These glycans play a critical role in stabilizing the fibrils and protecting them from proteolytic degradation and immune clearance [11, 12]. Therapeutic strategies targeting this complex, such as the peptide-antibody fusion zamubafusp alfa (AT-02), utilize polybasic peptides that bind to the negatively charged hypersulfated HS and the fibrils via electrostatic interactions [2, 4, 5]. This binding opsonizes the amyloid deposit, recruiting macrophages to phagocytose and clear the pathological material from tissues, thereby potentially restoring organ function in diseases like AL and ATTR amyloidosis [4, 6]. Additionally, this target is utilized for diagnostic imaging with agents like evuzamitide, which specifically localizes to the hypersulfated HS niche within amyloid deposits [5, 10].

Other names

Amyloid-associated heparan sulfate proteoglycansAmyloid-associated glycosaminoglycansAmyloid-associated HSPGPan-amyloid targetAmyloid deposit niche

Opsonization and macrophage-mediated phagocytic clearance of amyloid deposits