RT Journal Article
T1 Bifunctional carbazole derivatives for simultaneous therapy and fluorescence imaging in prion disease murine cell models
A1 Staderini, Matteo
A1 Vanni, Silvia
A1 Colini Baldeschi, Arianna
A1 Zattoni, Marco
A1 Celauro, Luigi
A1 Ferracin, Chiara
A1 Bistaffa, Edoardo
A1 Moda, Fabio
A1 Pérez, Daniel I.
A1 Martínez, Ana
A1 Martín Carmona, María Antonia
A1 Martín Cámara, Olmo
A1 Cores Esperón, Ángel
A1 Bianchini, Giulia
A1 Kammerer, Robert
A1 Menéndez Ramos, José Carlos
A1 Legname, Giuseppe
A1 Bolognesi, Maria Laura
AB Prion diseases are characterized by the self-assembly of pathogenic misfolded scrapie isoforms (PrPSc) of the cellular prion protein (PrPC). In an effort to achieve a theranostic profile, symmetrical bifunctional carbazole derivatives were designed as fluorescent rigid analogues of GN8, a pharmacological chaperone that stabilizes the native PrPC conformation and prevents its pathogenic conversion. A focused library was synthesized via a four- step route, and a representative member was confirmed to have native fluorescence, including a band in the near- infrared region. After a cytotoxicity study, compounds were tested on the RML-infected ScGT1 neuronal cell line, by monitoring the levels of protease-resistant PrPSc. Small dialkylamino groups at the ends of the molecule were found to be optimal in terms of therapeutic index, and the bis-(dimethylaminoacetamido)carbazole derivative 2b was selected for further characterization. It showed activity in two cellClines infected with the mouse-adapted RML strain (ScGT1 and ScN2a). Unlike GN8, 2b did not affect PrP levels, which represents a potential advantage in terms of toxicity. Amyloid Seeding Assay (ASA) experiments showed the capacity of 2b to delay the aggregation of recombinant mouse PrP. Its ability to interfere with the amplification of the scrapie RML strain by Protein Misfolding Cyclic Amplification (PMCA) was shown to be higher than that of GN8, although 2b did not inhibit the amplification of human vCJD prion. Fluorescent staining of PrPSc aggregates by 2b was confirmed in living cells. 2b emerges as an initial hit compound for further medicinal chemistry optimization towards strain- independent anti-prion compounds.
PB Elsevier
SN 0223-5234
YR 2022
FD 2022-11-15
LK https://hdl.handle.net/20.500.14352/72702
UL https://hdl.handle.net/20.500.14352/72702
LA eng
NO CRUE-CSIC (Acuerdos Transformativos 2022)
NO Ministerio de Ciencia e Innovación (MICINN)
DS Docta Complutense
RD 20 abr 2025