Molecular Insights into the Inhibition of Dialysis-Related β2m Amyloidosis Orchestrated by a Bispidine Peptidomimetic Analogue.

Abstract

Dialysis-related amyloidosis (DRA) is considered an inescapable consequence of renal failure. Upon prolonged hemodialysis, it involves accumulation of toxic β2-microglobulin (β2m) amyloids in bones and joints. Current treatment methods are plagued with high cost, low specificity, and low capacity. Through our in vitro and in cellulo studies, we introduce a peptidomimetic-based approach to help develop future therapeutics against DRA. Our study reports the ability of a nontoxic, core-modified, bispidine peptidomimetic analogue "B(LVI)2" to inhibit acid-induced amyloid fibrillation of β2m (Hβ2m). Using thioflavin-T, sodium dodecyl sulfate-polyacrylamide gel electrophoresis, and transmission electron microscopy analysis, we demonstrate that B(LVI)2 delays aggregation lag time of Hβ2m amyloid fibrillation and reduces the yield of Hβ2m amyloid fibrils in a dose-dependent manner. Our findings suggest a B(LVI)2-orchestrated alteration in the route of Hβ2m amyloid fibrillation resulting in the formation of noncytotoxic, morphologically distinct amyloid-like species. Circular dichroism data show gradual sequestration of Hβ2m species in a soluble nonamyloidogenic noncytotoxic conformation in the presence of B(LVI)2. Dynamic light scattering measurements indicate incompetence of Hβ2m species in the presence of B(LVI)2 to undergo amyloid-competent intermolecular associations. Overall, our study reports the antifibrillation property of a novel peptidomimetic with the potential to bring a paradigm shift in therapeutic approaches against DRA.