Integrating in vitro and in silico approaches to evaluate the "dual functionality" of palmatine chloride in inhibiting and disassembling Tau-derived VQIVYK peptide fibrils

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dc.contributor.author Haja, Esraa
dc.contributor.author Loseva, Yelena
dc.contributor.author Guru, Krishnakumar Viswanathan
dc.contributor.author Pichinuk, Edward
dc.contributor.author Engel, Hamutal
dc.contributor.author Raveh, Avi
dc.contributor.author Gazit, Ehud
dc.contributor.author Segal, Daniel
dc.date.accessioned 2018-04-18T12:09:50Z
dc.date.available 2018-04-18T12:09:50Z
dc.date.issued 2018-04
dc.identifier.citation Haja, Esraa; Loseva, Yelena; Guru Krishna Kumar, V.; Pichinuk, Edward; Engel, Hamutal; Raveh, Avi; Gazit, Ehud and Segal, Daniel, "Integrating in vitro and in silico approaches to evaluate the "dual functionality" of palmatine chloride in inhibiting and disassembling Tau-derived VQIVYK peptide fibrils", Biochimica et Biophysica Acta (BBA) - General Subjects, DOI: 10.1016/j.bbagen.2018.04.001, Vol.1862, No.7, pp. 1565-1575, Apr. 2018. en_US
dc.identifier.issn 0006-3002
dc.identifier.uri http://dx.doi.org/10.1016/j.bbagen.2018.04.001
dc.identifier.uri https://repository.iitgn.ac.in/handle/123456789/3607
dc.description.abstract Background Alzheimer's disease (AD) is the most common neurodegenerative disorder which is characterized by the deposits of intra-cellular tau protein and extra-cellular amyloid-β (Aβ) peptides in the human brain. Understanding the mechanism of protein aggregation and finding compounds that are capable of inhibiting its aggregation is considered to be highly important for disease therapy. Methods We used an in vitro High-Throughput Screening for the identification of potent inhibitors of tau aggregation using a proxy model; a highly aggregation-prone hexapeptide fragment 306VQIVYK311 derived from tau. Using ThS fluorescence assay we screened a library of 2401 FDA approved, bio-active and natural compounds in attempt to find molecules which can efficiently modulate tau aggregation. Results Among the screened compounds, palmatine chloride (PC) alkaloid was able to dramatically reduce the aggregation propensity of PHF6 at sub-molar concentrations. PC was also able to disassemble preformed aggregates of PHF6 and reduce the amyloid content in a dose-dependent manner. Insights obtained from MD simulation showed that PC interacted with the key residues of PHF6 responsible for β-sheet formation, which could likely be the mechanism of inhibition and disassembly. Furthermore, PC could effectively inhibit the aggregation of full-length tau and disassemble preformed aggregates. Conclusions We found that PC possesses “dual functionality” towards PHF6 and full-length tau, i.e. inhibit their aggregation and disassemble pre-formed fibrils. General significance The “dual functionality” of PC is valuable as a disease modifying strategy for AD, and other tauopathies, by inhibiting their progress and reducing the effect of fibrils already present in the brain.
dc.description.statementofresponsibility by Esraa Haj, Yelena Losev, V.Guru Krishna Kumar, Edward Pichinuk, Hamutal Engel, Avi Raveh, EhudGazit and DanielSegal
dc.format.extent Vol.1862, No.7, pp. 1565-1575
dc.language.iso en en_US
dc.publisher Elsevier en_US
dc.subject Aggregation modulator en_US
dc.subject Amyloid en_US
dc.subject High-Throughput Screening en_US
dc.subject Palmatine en_US
dc.subject PHF6 peptide en_US
dc.subject Tau protein en_US
dc.title Integrating in vitro and in silico approaches to evaluate the "dual functionality" of palmatine chloride in inhibiting and disassembling Tau-derived VQIVYK peptide fibrils en_US
dc.type Article en_US
dc.relation.journal BBA - Biochimica et Biophysica Acta


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