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

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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.

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.

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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.

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Authors and Affiliations

  1. Centre for Healthcare Science and Technology, IIEST, Shibpur, P.O. Botanic Garden, Howrah, West Bengal, 711103, India

    Sutapa Som Chaudhury, Jaya Sil & Chitrangada Das Mukhopadhyay

  2. Structural Biology & Bioinformatics Division, CSIR-IICB, Kolkata, 4, S.C. Mallick Road, Jadavpur, Kolkata, West Bengal, 700032, India

    Achinta Sannigrahi & Krishnananda Chattopadhyay

  3. Department of Chemical Sciences, IISER Kolkata, Mohanpur, Nadia, West Bengal, 741246, India

    Mridula Nandi & Priyadarsi De

  4. Department of Chemistry, IIT Kharagpur, Kharagpur, West Bengal, 721302, India

    Vipin K. Mishra & Sabyashachi Mishra

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  1. Sutapa Som Chaudhury
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Som Chaudhury, S., Sannigrahi, A., Nandi, M. et al. A Novel PEGylated Block Copolymer in New Age Therapeutics for Alzheimer’s Disease. Mol Neurobiol 56, 6551–6565 (2019). https://doi.org/10.1007/s12035-019-1542-1

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