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Selection of DNA Aptamer That Blocks the Fibrillogenesis of a Proteolytic Amyloidogenic Fragment of β 2 m.
Therapeutic Apheresis and Dialysis 2018 Februrary
Dialysis-related amyloidosis (DRA) is a severe complication of hemodialysis that results in progressive destruction of bones and joints. Elevated concentrations of the β2 -microglobulin (β2 m) level in the serum of subjects on hemodialysis promote the formation of amyloid fibrils in osteoarticular tissues. β2 m lacking the N-terminal six residues of the mature protein (ΔN6β2 m) constitutes 25-30% of β2 m in ex vivo DRA amyloid. Unlike full-length wild-type β2 m, ΔN6β2 m forms amyloid fibrils at neutral pH in vitro. However, the role of ΔN6β2 m in DRA is, at present, poorly understood. In the present study, we screened novel phosphorothioate-modified aptamers directed against ΔN6β2 m using combinatorial chemistry in vitro. We identified 11 ΔN6β2 m aptamers; among the identified aptamers, clone #2, #8, and #10 aptamers had higher binding affinity to ΔN6β2 m than the others. Biolayer interferometry analysis revealed that KD values of clone #2, #8, and #10 aptamers were 56, 23, and 44 nM, respectively. Furthermore, the clone #8 aptamer inhibited fibril formation in a dose-dependent manner, as assessed by Thioflavin T fluorescence assay. Fibrils formed from ΔN6β2 m bind to Congo red, displaying changes in the absorbance spectrum of the dye characteristic of binding to amyloid fibrils, which was completely blocked by treatment with clone #8 aptamer. These results suggest the potential of ΔN6β2 m aptamers as tools for elucidating co-assembly mechanisms in amyloid formation.
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