Engineered polymer nanoparticles containing hydrophobic dipeptide for inhibition of amyloid-β fibrillation.
Protein aggregation into amyloid fibrils is implicated in the pathogenesis of many neurodegenerative diseases. Engineered nanoparticles have emerged as a potential approach to alter the kinetics of protein fibrillation process. Yet, there are only a few reports describing the use of nanoparticles for inhibition of amyloid-β 40 (Aβ(40)) peptide aggregation, involved in Alzheimer's disease (AD). In the present study, we designed new uniform biocompatible amino-acid-based polymer nanoparticles containing hydrophobic dipeptides in the polymer side chains. The dipeptide residues were designed similarly to the hydrophobic core sequence of Aβ. Poly(N-acryloyl-L-phenylalanyl-L-phenylalanine methyl ester) (polyA-FF-ME) nanoparticles of 57 ± 6 nm were synthesized by dispersion polymerization of the monomer A-FF-ME in 2-methoxy ethanol, followed by precipitation of the obtained polymer in aqueous solution. Cell viability assay confirmed that no significant cytotoxic effect of the polyA-FF-ME nanoparticles on different human cell lines, e.g., PC-12 and SH-SY5Y, was observed. A significantly slow secondary structure transition from random coil to β-sheets during Aβ(40) fibril formation was observed in the presence of these nanoparticles, resulting in significant inhibition of Aβ(40) fibrillation kinetics. However, the polyA-FF-ME analogous nanoparticles containing the L-alanyl-L-alanine (AA) dipeptide in the polymer side groups, polyA-AA-ME nanoparticles, accelerate the Aβ(40) fibrillation kinetics. The polyA-FF-ME nanoparticles and the polyA-AA-ME nanoparticles may therefore contribute to a mechanistic understanding of the fibrillation process, leading to the development of therapeutic strategies against amyloid-related diseases.
Department of Chemistry, Bar-Ilan Institute of Nanotechnology and Advanced Materials, Ramat-Gan 52900, Israel.
Hadas
H
Skaat
Ravit
R
Chen
Igor
I
Grinberg
Shlomo
S
Margel
D000596:Amino Acids / Q000737:chemistry; D016229:Amyloid beta-Peptides / Q000037:antagonists & inhibitors*; D001672:Biocompatible Materials / Q000138:chemical synthesis* / Q000494:pharmacology; D045744:Cell Line, Tumor; D002470:Cell Survival / Q000187:drug effects; D004151:Dipeptides / Q000737:chemistry*; D004952:Esters; D006801:Humans; D057927:Hydrophobic and Hydrophilic Interactions; D007700:Kinetics; D009682:Magnetic Resonance Spectroscopy; D053758:Nanoparticles / Q000737:chemistry*; D010316:Particle Size; D010446:Peptide Fragments / Q000037:antagonists & inhibitors*; D010455:Peptides / Q000138:chemical synthesis* / Q000494:pharmacology; D010649:Phenylalanine / Q000031:analogs & derivatives*; D011108:Polymers / Q000138:chemical synthesis* / Q000494:pharmacology; D017433:Protein Structure, Secondary; D017550:Spectroscopy, Fourier Transform Infrared
D000596:Amino Acids; D016229:Amyloid beta-Peptides; D001672:Biocompatible Materials; D004151:Dipeptides; D004952:Esters; D010446:Peptide Fragments; D010455:Peptides; D011108:Polymers; C078592:amyloid beta-protein (1-40); C577459:poly(N-acryloyl-L-phenylalanyl-L-phenylalanine methyl ester); D010649:Phenylalanine