Pan-amyloid fibrils and associated hypersulfated glycosaminoglycans

Pan-amyloid fibrils and associated hypersulfated glycosaminoglycans (GAGs) constitute a universal pathological feature of amyloidosis, a group of diseases characterized by the extracellular deposition of misfolded proteins. While the precursor proteins vary (e.g., light chains in AL or transthyretin in ATTR), the resulting fibrils share a common cross-beta sheet structure and are invariably associated with hypersulfated GAGs, particularly heparan sulfate (Wall et al., 2022, Molecules). These GAGs are believed to play a critical role in the nucleation, stabilization, and protection of amyloid fibrils from proteolytic degradation (Townsend et al., 2023, Journal of Nuclear Medicine). Because these components are present regardless of the specific protein type, they serve as a 'pan-amyloid' target for both diagnostic and therapeutic applications. Modern radiopharmaceuticals like evuzamitide (AT-01) utilize synthetic peptides that bind with high affinity to these sites, allowing for the first-ever comprehensive imaging of systemic amyloid burden across multiple organs (Wall et al., 2023, Blood). Therapeutic candidates are also being developed to bind this target and recruit the innate immune system to phagocytose and clear the deposits, potentially reversing organ dysfunction (Attralus Pipeline, 2024).

Other names

Amyloid-associated glycosaminoglycansAmyloid-associated GAGsMisfolded protein aggregatesSystemic amyloid depositsHypersulfated heparan sulfate proteoglycans

Binding to the common structural motifs of misfolded amyloid fibrils and the negatively charged hypersulfated glycosaminoglycans to enable diagnostic visualization or immune-mediated clearance of deposits.