Title
Blocking Oligomeric Insulin Amyloid Fibrillation via Perylenebisimides Containing Dipeptide Tentacles
Author
Sayan Roy Chowdhury, Subrata Mondal, Parameswar Krishnan Iyer
Year
2018
Journal
ACS Biomaterials Science & Engineering
Abstract
Molecular motifs that could interfere with amyloid fibrillation via non covalent interactions are very vital towards aberrant protein aggregation and related human diseases. Mutual aggregation ensues in the presence of these structural motifs and nucleation on the particle surface leads to inhibition of the fibrillization process. This modular process generates a new generation of inhibitory reagents. Oligomers are the primary toxic species that initiate pathogenic aggregation leading to toxic β-sheet rich structures. To inhibit these toxic oligomers, two dipeptide linked perylenebisimide isomers (PAPAP and APPPA) are developed as selective modulators for insulin fibrillization. Early insulin aggregates are adsorbed into the modulator surface and stabilizes soluble oligomeric aggregates. Fibrillation and inhibition were examined by Thioflavin T (ThT) assay in the presence and the absence of both inhibitors, PAPAP and APPPA. Conformational modulation using far UV circular dichroism studies also high-lighted their role as an aggregation inhibitor via reduction of α-helix into β-sheet along with increased random coil contents. Moreover, the inhibitory effects were more pronounced due to the varying multiple non covalent interaction ability of these isomers, a performance well beyond all known modulators with respect to selectivity and efficiency, with the more aggregation prone derivative due to higher probability of a hydrophobic encounter between the protein and the molecular modulator. These results also lead to the elucidation of insulin fibril regulating mechanism via selective non covalent binding and provide fundamental insights into the chemistry of peptide-based probes as tools for developing next-generation therapeutics.
Instrument
J-1500
Keywords
Circular dichroism, Secondary structure, Chemical stability, Aggregation, Biochemistry, Materials