Extracellular amyloid fibrils and associated glycosaminoglycan-rich fibril surfaces

Extracellular amyloid fibrils and associated glycosaminoglycan-rich fibril surfaces constitute the structural hallmark of amyloidosis, a group of diseases characterized by the deposition of insoluble protein aggregates in tissues. These deposits are composed of misfolded precursor proteins—such as immunoglobulin light chains (AL) or transthyretin (ATTR)—intertwined with extracellular matrix components, particularly hypersulfated heparan sulfate glycosaminoglycans (GAGs) [1, 13]. The GAGs provide a highly electronegative surface that is common to virtually all types of amyloid, making it an ideal pan-amyloid target for diagnostic and therapeutic intervention [5, 6]. Drugs targeting this complex, such as the radiotracer 124I-evuzamitide (AT-01) and the therapeutic fusion protein AT-02, utilize polybasic peptides to bind the charged fibril surfaces [1, 4]. In a therapeutic context, these agents function as opsonins that label the amyloid for recognition by the innate immune system, triggering macrophage-mediated phagocytosis and clearance of the deposits [4, 14]. This approach aims to reduce the total amyloid burden and improve organ function, addressing the unmet need for treatments that directly remove existing tissue deposits in systemic and localized amyloid diseases [12, 14].

Other names

Amyloid depositsAmyloid-associated glycosaminoglycansAmyloid-associated GAGsPan-amyloid targetAmyloid-associated heparan sulfate proteoglycans

Binding to electronegative surfaces of amyloid fibrils and associated glycosaminoglycans to facilitate imaging or immune-mediated clearance via opsonization and macrophage-mediated phagocytosis.