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The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein

Prion diseases involve misfolded and highly infectious aggregates of prion protein (PrP(Sc)) which forms amyloid plaques leading to fatal neurodegeneration. The absence of clinically proven therapeutics makes the discovery of effective remedial interventions a prime concern. Herein, we report novel...

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Autores principales: Sirohi, Preeti Rana, Kumari, Anchala, Admane, Nikita, Somvanshi, Pallavi, Grover, Abhinav
Formato: Online Artículo Texto
Lenguaje:English
Publicado: The Royal Society of Chemistry 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037109/
https://www.ncbi.nlm.nih.gov/pubmed/35479435
http://dx.doi.org/10.1039/d1ra01891d
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author Sirohi, Preeti Rana
Kumari, Anchala
Admane, Nikita
Somvanshi, Pallavi
Grover, Abhinav
author_facet Sirohi, Preeti Rana
Kumari, Anchala
Admane, Nikita
Somvanshi, Pallavi
Grover, Abhinav
author_sort Sirohi, Preeti Rana
collection PubMed
description Prion diseases involve misfolded and highly infectious aggregates of prion protein (PrP(Sc)) which forms amyloid plaques leading to fatal neurodegeneration. The absence of clinically proven therapeutics makes the discovery of effective remedial interventions a prime concern. Herein, we report novel prion intervention by the polyphenolic phytoalexin, polydatin which binds with moderate affinity to the recombinant protease resistant core of human prion protein, encompassing the sequence 90–231 (rPrP(res)) and inhibits its conversion into the highly neurotoxic forms. An extensive evaluation using biophysical techniques revealed that polydatin incubated rPrP(res) samples generate off-pathway oligomers having reduced cross-β sheet signature, and relatively smaller in size than the native rPrP(res) oligomers. The detailed structural analysis using molecular dynamics simulations elucidated the induction of antagonistic mobilities in the β2–α2 loop, α3 helix and the N-terminal amyloidogenic region of prions. This study puts forward novel prion fibrillogenesis inhibitory potential of polydatin, specifically by stabilizing the N-terminal amyloidogenic region. Collectively our results affirm the importance of polydatin in crippling the prion pathogenesis and may serve as a structural scaffold for designing novel therapeutic agents targeting amyloidogenic transition in prions.
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spelling pubmed-90371092022-04-26 The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein Sirohi, Preeti Rana Kumari, Anchala Admane, Nikita Somvanshi, Pallavi Grover, Abhinav RSC Adv Chemistry Prion diseases involve misfolded and highly infectious aggregates of prion protein (PrP(Sc)) which forms amyloid plaques leading to fatal neurodegeneration. The absence of clinically proven therapeutics makes the discovery of effective remedial interventions a prime concern. Herein, we report novel prion intervention by the polyphenolic phytoalexin, polydatin which binds with moderate affinity to the recombinant protease resistant core of human prion protein, encompassing the sequence 90–231 (rPrP(res)) and inhibits its conversion into the highly neurotoxic forms. An extensive evaluation using biophysical techniques revealed that polydatin incubated rPrP(res) samples generate off-pathway oligomers having reduced cross-β sheet signature, and relatively smaller in size than the native rPrP(res) oligomers. The detailed structural analysis using molecular dynamics simulations elucidated the induction of antagonistic mobilities in the β2–α2 loop, α3 helix and the N-terminal amyloidogenic region of prions. This study puts forward novel prion fibrillogenesis inhibitory potential of polydatin, specifically by stabilizing the N-terminal amyloidogenic region. Collectively our results affirm the importance of polydatin in crippling the prion pathogenesis and may serve as a structural scaffold for designing novel therapeutic agents targeting amyloidogenic transition in prions. The Royal Society of Chemistry 2021-07-28 /pmc/articles/PMC9037109/ /pubmed/35479435 http://dx.doi.org/10.1039/d1ra01891d Text en This journal is © The Royal Society of Chemistry https://creativecommons.org/licenses/by-nc/3.0/
spellingShingle Chemistry
Sirohi, Preeti Rana
Kumari, Anchala
Admane, Nikita
Somvanshi, Pallavi
Grover, Abhinav
The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein
title The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein
title_full The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein
title_fullStr The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein
title_full_unstemmed The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein
title_short The polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein
title_sort polyphenolic phytoalexin polydatin inhibits amyloid aggregation of recombinant human prion protein
topic Chemistry
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9037109/
https://www.ncbi.nlm.nih.gov/pubmed/35479435
http://dx.doi.org/10.1039/d1ra01891d
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