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

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