Pathological amyloid fibrils and associated high charge-density heparan sulfate glycosaminoglycans

Pathological amyloid fibrils and associated high charge-density heparan sulfate glycosaminoglycans (HS GAGs) constitute the structural core of amyloid deposits found in systemic and localized amyloidosis. Amyloidosis involves the misfolding of soluble proteins into insoluble fibrils that accumulate in organs such as the heart, kidneys, and liver, leading to progressive organ failure (Wall et al., 2015). HS GAGs are universal components of these deposits, acting as scaffolds that promote fibril formation, stabilize the aggregates against proteolytic degradation, and shield them from immune clearance (Snow et al., 1987). This complex is a significant therapeutic target because it presents a common pan-amyloid signature across different types of the disease, including AL and ATTR amyloidosis. Drugs targeting this complex, such as the fusion protein AT-03, are designed to bind specifically to the unique conformational epitopes of the fibrils and the hypersulfated regions of the associated GAGs (Attralus Therapeutics, 2023). Once bound, these agents facilitate the recruitment of macrophages to the site of deposition, promoting the removal of existing amyloid through phagocytosis. This mechanism offers a potential advantage over therapies that only inhibit the production of precursor proteins, as it directly addresses the existing burden of disease in affected tissues.

Other names

Amyloid-associated glycosaminoglycansAmyloid-HS GAG complexPan-amyloid targetAmyloid depositsHypersulfated heparan sulfate

Binding to the common structural motifs of amyloid fibrils and associated hypersulfated heparan sulfate glycosaminoglycans to induce immune-mediated clearance via phagocytosis.