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A natural heptameric peptide exhibits multifaceted inhibitory role in the fibrillation pathway of amyloid-beta
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  • Rajanya Bhattacharyya,
  • Sayan Bhattacharjee,
  • Bani Pathak,
  • JAYATI SENGUPTA
Rajanya Bhattacharyya
Indian Institute of Chemical Biology CSIR
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Sayan Bhattacharjee
Indian Institute of Chemical Biology CSIR
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Bani Pathak
Indian Institute of Chemical Biology CSIR
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JAYATI SENGUPTA
Indian Institute of Chemical Biology CSIR
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Abstract

Background and Purpose Alzheimer’s disease (AD) pathogenesis involves amyloid-β (Aβ) aggregation where the intermediate oligomers are considered the prime toxic species. Here, we aimed to identify an effective peptide sequence from a medicinal plant-derived enzyme having anti-amyloidogenic properties against Aβ. Experimental Approach LC-MS/MS followed by computational analysis identified the active peptide (termed here as Pactive). Visualization techniques along with biophysical and biochemical approaches were used to determine the anti-amyloidogenic potency of the purified enzyme and peptides identified from the enzyme. Cytotoxicity was measured on SHSY-5Y cell lines. Interaction studies were done with bio-layer interferometry (BLI) and bio-stability of the peptide was assessed by NMR. Pactive induced conformational alterations of Aβ monomer and oligomers was determined with DSC and NMR. Key Results A small heptameric peptide (Pactive) identified form a medicinal plant-derived fibrinolytic enzyme proved to be a multifunctional inhibitor against Aβ aggregation. The results suggested that Pactive arrests Aβ molecules in non-toxic off-pathway oligomers that can no longer participate in the cytotoxic fibrillation pathway. Mechanistically, Pactive binding induces conformational alterations in the Aβ molecule, thus modulating its hydrophobicity, one of the key players in inducing aggregation. Conclusions and Implications The study identified a natural peptide Pactive (GFLLHQK) that displays potential anti-amyloidogenic properties against Aβ aggregation. The bio-stability of Pactive in human blood serum as well as its non-toxic nature makes it a promising therapeutic candidate against Alzheimer’s, for which no disease-modifying treatments are available till date.