TY  - JOUR
AU  - Zaccagnini, Ludovica
AU  - Rossetti, Giulia
AU  - Tran, Thanh Hoa
AU  - Salzano, Giulia
AU  - Gandini, Annachiara
AU  - Colini Baldeschi, Arianna
AU  - Bolognesi, Maria Laura
AU  - Carloni, Paolo
AU  - Legname, Giuseppe
TI  - In silico/in vitro screening and hit evaluation identified new phenothiazine anti-prion derivatives
JO  - European journal of medicinal chemistry
VL  - 196
SN  - 0223-5234
CY  - Amsterdam [u.a.]
PB  - Elsevier71544
M1  - FZJ-2020-03077
SP  - 112295
PY  - 2020
AB  - 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.
LB  - PUB:(DE-HGF)16
C6  - 32325366
UR  - <Go to ISI:>//WOS:000530224900004
DO  - DOI:10.1016/j.ejmech.2020.112295
UR  - https://juser.fz-juelich.de/record/884076
ER  -