Modulating the assembly of medically relevant peptides and proteins via macromolecular engineering is an important step in modifying their overall pathological effects. The synthesis of polymer-peptide conjugates composed of the amyloidogenic Alzheimer peptide, Aβ1-40 , and poly(oligo(ethylene glycol)m acrylates) (m = 2,3) with different molecular weights (Mn = 1400-6600 g mol-1 ) is presented here. The challenging conjugation of a synthetic polymer to an in situ aggregating protein is established via two different coupling strategies, only successful for polymers with molecular weights not exceeding 6600 g mol-1 , relying on resin-based synthesis or solution-based coupling chemistries. The conjugates are characterized by high-performance liquid chromatography and matrix-assisted laser desorption ionization time-of-flight mass spectrometry. The aggregation of these polymer-Aβ1-40 conjugates, as monitored via thioflavine-T (ThT)-fluorescence spectroscopy, is accelerated mainly upon attaching the polymers. However, the appearance of the observed fibrils is different from those composed of native Aβ1-40, specifically with respect to length and morphology of the obtained aggregates. Instead of long, unbranched fibrils characteristic for Aβ1-40 , bundles of short aggregates are observed for the conjugates. Finally, the ThT kinetics and morphologies of Aβ1-40 fibrils formed in the presence of the conjugates give some mechanistic insights.
Keywords: aggregation; amyloid β; coupling; fibrils; polymer-peptide conjugates.
© 2019 The Authors. Published by WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim.