Synthesis and Aggregation of Polymer-Amyloid β Conjugates.

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, Aβ , and poly(oligo(ethylene glycol) acrylates) (m = 2,3) with different molecular weights (M = 1400-6600 g mol ) 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 , 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-Aβ 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 Aβ specifically with respect to length and morphology of the obtained aggregates. Instead of long, unbranched fibrils characteristic for Aβ , bundles of short aggregates are observed for the conjugates. Finally, the ThT kinetics and morphologies of Aβ fibrils formed in the presence of the conjugates give some mechanistic insights.