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@ARTICLE{Zaccagnini:884076,
author = {Zaccagnini, Ludovica and Rossetti, Giulia and Tran, Thanh
Hoa and Salzano, Giulia and Gandini, Annachiara and Colini
Baldeschi, Arianna and Bolognesi, Maria Laura and Carloni,
Paolo and Legname, Giuseppe},
title = {{I}n silico/in vitro screening and hit evaluation
identified new phenothiazine anti-prion derivatives},
journal = {European journal of medicinal chemistry},
volume = {196},
issn = {0223-5234},
address = {Amsterdam [u.a.]},
publisher = {Elsevier71544},
reportid = {FZJ-2020-03077},
pages = {112295},
year = {2020},
abstract = {Prion diseases or transmissible spongiform encephalopathies
(TSEs) are a group of rare neurodegenerative disorders. TSEs
are characterized by the accumulation of prions (PrPSc) that
represent pathological isoforms of the physiological
cellular prion protein PrPC. Although the conversion of PrPC
to PrPSc is still not completely understood, blocking this
process may lead to develop new therapies. Here, we have
generated a pharmacophore model, based on anti-prion
molecules reported in literature to be effective in
phenotypic assay. The model was used to conduct a virtual
screen of commercial compound databases that selected a
small library of ten compounds. These molecules were then
screened in mouse neuroblastoma cell line chronically
infected with prions (ScN2a) after excluding neurotoxicity.
1 has been identified as the therapeutic hit on the basis of
the following evidence: chronic treatments of ScN2a cells
using 1 eliminate PrPSc loaded in both Western blotting
analysis and Real-Time Quaking-Induced Conversion (RT-QuIC)
assay. We also proposed the mechanism of action of 1 by
which it has the ability to bind PrPC and consequentially
blocks prion conversion. Herein we describe the results of
these efforts.},
cin = {IAS-5 / INM-9 / JSC},
ddc = {610},
cid = {I:(DE-Juel1)IAS-5-20120330 / I:(DE-Juel1)INM-9-20140121 /
I:(DE-Juel1)JSC-20090406},
pnm = {574 - Theory, modelling and simulation (POF3-574) / 511 -
Computational Science and Mathematical Methods (POF3-511)},
pid = {G:(DE-HGF)POF3-574 / G:(DE-HGF)POF3-511},
typ = {PUB:(DE-HGF)16},
pubmed = {32325366},
UT = {WOS:000530224900004},
doi = {10.1016/j.ejmech.2020.112295},
url = {https://juser.fz-juelich.de/record/884076},
}