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Serendipitous inhibition of Aβ and rVλ6Wil amyloid fibril growth by bi-functional peptides

Amyloidosis is characterized by the aggregation of partially misfolded proteins or peptides as fibrils that deposit in organs and tissues resulting in dysfunction and death. We have previously identified a series of amyloid-targeting, synthetic, polybasic peptides, such as peptide p5, that specifically interact with numerous forms of synthetic amyloid fibrils and human amyloid extracts in vitro as well as systemic inflammation-associated (AA) amyloid deposits in vivo [1]. Although there has been great progress in the development of amyloid-targeting immunotherapeutic agents designed to selectively bind amyloid and facilitate their removal [2], at present, there are no amyloid-directed therapeutics that successfully prevent the growth or extension of amyloid fibrils. Indeed, the process of fibril growth post nucleation is widely considered to be kinetically and thermodynamically remarkably favorable and, as such, potentially unstoppable. However, decreasing the rate of fibrillogenesis or amyloid growth is an important, clinically relevant, intervention point and would represent another treatment option for patients with amyloidosis. To address this, we have developed novel, bi-functional amyloid binding peptides originally designed to enhance the circulating lifetime of peptide p5 by the addition of albumin-binding peptide sequences. Using a battery of in vitro fibrillogenesis assays, certain peptides have been shown, serendipitously, to inhibit fibril formation of two amyloidogenic precursors: Ab(1–40) and a recombinant human 6 variable domain derived from patient Wil (rV 6Wil). Data from molecular dynamics simulations, using a model of Ab amyloid fibril as the substrate [3], suggest that these peptides may serve as inhibitors of fibril elongation by ‘‘capping’’ the fibril end, a site of potential precursor protein recruitment. Materials and methods