Amyloid fibrils and hypersulfated glycosaminoglycans

Amyloid fibrils and hypersulfated glycosaminoglycans (GAGs) are the primary structural components of amyloid deposits, which are the hallmark of various protein-misfolding diseases known as amyloidosis [3, 4]. These deposits consist of insoluble protein fibrils and associated extracellular matrix components, most notably hypersulfated heparan sulfate proteoglycans, which are ubiquitously present across different amyloid types (e.g., AL, ATTR, AA) [5, 10]. The GAGs play a critical role in stabilizing the fibrils and promoting their accumulation in tissues, leading to organ dysfunction [3, 8]. This complex serves as a "pan-amyloid" target for both diagnostic and therapeutic interventions [11, 14]. Diagnostic agents like evuzamitide (AT-01) utilize radiolabeled polybasic peptides to bind the electrostatic motifs of the GAG-fibril complex, allowing for the visualization of amyloid burden via PET/CT [11, 22]. Therapeutic candidates such as zamubafusp alfa (AT-02) and AT-04 are antibody-peptide fusions that bind to these deposits and opsonize them, triggering macrophage-mediated phagocytosis and clearance of the amyloid from organs [10, 15]. By facilitating the removal of existing amyloid, these therapies aim to reverse tissue damage and improve clinical outcomes for patients with systemic and neurodegenerative amyloid diseases [13, 16].

Other names

Amyloid fibrils and hypersulfated glycosaminoglycans in amyloid depositsPan-amyloid targetAmyloid depositsHypersulfated heparan sulfate proteoglycans in amyloidAmyloid-associated glycosaminoglycansAmyloid fibril-GAG complex

The target is addressed through the electrostatic binding of polybasic peptides to negatively charged hypersulfated glycosaminoglycans and acidic residues on amyloid fibrils [3, 4]. Imaging agents like evuzamitide (AT-01) use this binding to localize radiotracers to amyloid deposits for detection via PET/CT [11, 22]. Therapeutic agents like zamubafusp alfa (AT-02) and AT-04 utilize this binding to opsonize amyloid deposits, thereby inducing macrophage-mediated phagocytosis and clearance of the fibrils from tissues [5, 10, 15].