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A Novel PEGylated Block Copolymer in New Age Therapeutics for Alzheimer’s Disease

  • Sutapa Som Chaudhury
  • Achinta Sannigrahi
  • Mridula Nandi
  • Vipin K. Mishra
  • Priyadarsi De
  • Krishnananda Chattopadhyay
  • Sabyashachi Mishra
  • Jaya Sil
  • Chitrangada Das MukhopadhyayEmail author
Article
  • 84 Downloads

Abstract

The amyloid cascade hypothesis dealing with the senile plaques is until date thought to be one of the causative pathways leading to the pathophysiology of Alzheimer’s disease (AD). Though many aggregation inhibitors of misfolded amyloid beta (Aβ42) peptide have failed in clinical trials, there are some positive aspects of the designed therapeutic peptides for diseases involving proteinaceous aggregation. Here, we evaluated a smart design of side chain tripeptide (Leu-Val-Phe)-based polymeric inhibitor addressing the fundamental hydrophobic amino acid stretch “Lys-Leu-Val-Phe-Phe-Ala” (KLVFFA) of the Aβ42 peptide. The in vitro analyses performed through the thioflavin T (ThT) fluorescence assay, infrared spectroscopy, isothermal calorimetry, cytotoxicity experiments, and so on evinced a promising path towards the development of new age AD therapeutics targeting the inhibition of misfolded Aβ42 peptide fibrillization. The in silico simulations done contoured the mechanism of drug action of the present block copolymer as the competitive inhibition of aggregate-prone hydrophobic stretch of Aβ42.

Graphical abstract

The production of misfolded Aβ42 peptide from amyloid precursor protein initiates amyloidosis pathway which ends with the deposition of fibrils via the oligomerization and aggregation of Aβ42 monomers. The side chain tripeptide-based PEGylated polymer targets these Aβ42 monomers and oligomers inhibiting their aggregation. This block copolymer also binds and helps degrading the preformed fibrils of Aβ42.

Keywords

Alzheimer’s disease Amyloid beta peptide Fibrillization Inhibitor Peptidomimetics M.D. simulation 

Notes

Acknowledgements

We thank Mr. Kashinath Sahu at the Indian Institute of Science Education and Research (IISER), Kolkata, and Mr. Satyabrata Samaddar at the CSIR—Indian Institute of Chemical Biology (IICB), Kolkata, for the assistance with the FE-SEM and FT-IR work, respectively.

Funding

This research did not receive any specific grant from funding agencies in the public, commercial, or not-for-profit sectors.

Compliance with Ethical Standards

Conflicts of Interest

The authors declare that they have no conflict of interest.

Supplementary material

12035_2019_1542_MOESM1_ESM.pdf (1.4 mb)
ESM 1 (PDF 1479 kb).

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Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Sutapa Som Chaudhury
    • 1
  • Achinta Sannigrahi
    • 2
  • Mridula Nandi
    • 3
  • Vipin K. Mishra
    • 4
  • Priyadarsi De
    • 3
  • Krishnananda Chattopadhyay
    • 2
  • Sabyashachi Mishra
    • 4
  • Jaya Sil
    • 1
  • Chitrangada Das Mukhopadhyay
    • 1
    Email author
  1. 1.Centre for Healthcare Science and TechnologyIIEST, ShibpurHowrahIndia
  2. 2.Structural Biology & Bioinformatics DivisionCSIR-IICB, KolkataKolkataIndia
  3. 3.Department of Chemical SciencesIISER KolkataNadiaIndia
  4. 4.Department of ChemistryIIT KharagpurKharagpurIndia

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