Disruption of Amyloid Prion Protein Aggregates by Cationic Pyridylphenylene Dendrimers

Abstract

Disruption of amyloid protein aggregates is one of the potential therapies for treatment of neurodegenerative disorders such as prion diseases. Here, for the first time we report that pH-independent cationic pyridylphenylene dendrimers are able to disrupt amyloid protein aggregates at physiological pH as exemplified by inclusion bodies of ovine prion protein. The results show that exposure of inclusion bodies to the dendrimers leads to its partial disaggregation and release of the nanosize protein-dendrimer complexes. The complexes were characterized by SDS PAGE, DLS, and Western blotting methods. Thioflavin T fluorescence clearly demonstrated a decrease of amyloidogenic capability of the prion protein upon exposure to the dendrimers. The complexes formed are stable and do not show further aggregation.

Star Polymers Reduce Islet Amyloid Polypeptide Toxicity via Accelerated Amyloid Aggregation

“…10−13 For example, antiprion activity has been demonstrated by phosphorus dendrimers, maltose-based glycodendrimers (mPPI), poly(propyleneimine) PPI, and poly(ethylenimine) hyperbranched polymers. 12−20 Of the myriad forms of polymeric NPs, hyperbranched polymers and dendrimers have demonstrated strong efficacies as antiamyloid agents, 11,12,15,21−26 though anti-IAPP applications have only been explored recently. PPI glycodendrimers and lysine dendrimers have been investigated as anti-Aβ aggregation agents, 22,23 and hyperbranched PEG-based polymers with a dopamine moiety were found to be capable of inhibiting α-synuclein (αS) aggregation.…”

The Past 40 Years of Macromolecular Sciences: Reflections on Challenges in Synthetic Polymer and Material Science

“…In the pathway of aggregation, the monomeric and soluble proteins or peptides are converted into oligomers and finally into the amyloid fibrils, similar to the in vitro formation of protein fibrils . How are we able to understand and interfere with such processes as polymer scientists, similar to our well‐exploited strategies to design proper, but mostly artificial assembly systems (e.g., recent low‐molecular‐weight helix mimetics and polymers)? Based on the plethora of known assembly systems, their design, and the monitoring via new techniques (e.g., a recent technique by Meijer et.…”

Artificial chaperones based on thermoresponsive polymers recognize the unfolded state of the protein

“…Linear [13] and dendrimer [18][19][20] polyelectrolytes were also suggested as a prospective way to treat amyloid aggregation. The protective power of the polyelectrolyte was shown to depend on the nature of the charged groups (sulfated and sulfonated polymers are more efficient than polyphosphates [21] and polycarboxylates [15]), amount of the hydrophobic groups in the polymer chain [22], and degree of polymerization [15,21].…”