Proline-rich, polybasic peptides are a structurally distinct class of amyloid-reactive peptides

Systemic amyloidosis is a chronic, devastating illness caused by the build-up of misfolded proteins, leading to abdominothoracic organ dysfunction. Currently approved treatment options focus on preventing further amyloid accumulation. As such, there is a clinically unmet need for therapeutics that can opsonize tissue-deposited amyloid for clearance by phagocytic cells. We have developed a class of polybasic peptides that bind conserved properties of amyloid and amyloid-associated hypersulfated heparan sulfate, with high specificity. We have generated a novel structural class of polybasic peptides (termed PxR peptides) based on a proline-rich repeat strategy that demonstrates potency against amyloid.

Amyloid-reactivity and specificity were probed using amyloid-laden and control tissue sections from mice and humans. Amyloid binding to synthetic fibrils and human patient-derived amyloid extracts was quantified using immunosorbent assays. PxR peptide stability in mouse and human serum was quantified using a bioactivity assay.

PxR peptides were predicted to form a linear face of positive charges, which can bind with high specificity and potency to synthetic fibrils and amyloid extracts, and are resistant to serum proteases.

Polybasic PxR peptides offer additional resources as pan-amyloid binding peptides for effective delivery of bioactive and amyloid-clearing therapeutics to amyloid.