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Pyrazolones Activate the Proteasome by Gating Mechanisms and Protect Neuronal Cells from β‐Amyloid Toxicity
Author(s) -
Santoro Anna Maria,
Lanza Valeria,
Bellia Francesco,
Sbardella Diego,
Tundo Grazia R.,
Cannizzo Alessandra,
Grasso Giuseppe,
Arizzi Mariaconcetta,
Nicoletti Vincenzo G.,
Alcaro Stefano,
Costa Giosuè,
Pietropaolo Adriana,
Malgieri Gaetano,
D'Abrosca Gianluca,
Fattorusso Roberto,
GarcíaViñuales Sara,
Ahmed Ikhlas M. M.,
Coletta Massimiliano,
Milardi Danilo
Publication year - 2020
Publication title -
chemmedchem
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.817
H-Index - 100
eISSN - 1860-7187
pISSN - 1860-7179
DOI - 10.1002/cmdc.201900612
Subject(s) - proteasome , pyrazolones , chemistry , toxicity , microbiology and biotechnology , biochemistry , biology , organic chemistry , medicinal chemistry
Proteasome malfunction parallels abnormal amyloid accumulation in Alzheimer's Disease (AD). Here we scrutinize a small library of pyrazolones by assaying their ability to enhance proteasome activity and protect neuronal cells from amyloid toxicity. Tube tests evidenced that aminopyrine and nifenazone behave as 20S proteasome activators. Enzyme assays carried out on an “open gate” mutant (α3ΔN) proteasome demonstrated that aminopyrine activates proteasome through binding the α‐ring surfaces and influencing gating dynamics. Docking studies coupled with STD‐NMR experiments showed that H‐bonds and π‐π stacking interactions between pyrazolones and the enzyme play a key role in bridging α1 to α2 and, alternatively, α5 to α6 subunits of the outer α‐ring. Aminopyrine and nifenazone exhibit neurotrophic properties and protect differentiated human neuroblastoma SH‐SY5Y cells from β‐amyloid (Aβ) toxicity. ESI‐MS studies confirmed that aminopyrine enhances Aβ degradation by proteasome in a dose‐dependent manner. Our results suggest that some pyrazolones and, in particular, aminopyrine are promising compounds for the development of proteasome activators for AD treatment.