RT Journal Article
T1 From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects
A1 Pont, Caterina
A1 Ginex, Tiziana
A1 Griñán Ferré, Christian
A1 Scheiner, Matthias
A1 Mattellone, Alexia
A1 Martínez, Noemí
A1 Arce, Elsa M.
A1 Soriano Fernández, Yolanda
A1 Naldi, Marina
A1 Simone, Angela de
A1 Barenys, Marta
A1 Gómez Catalán, Jesús
A1 Pérez, Belén
A1 Sabate, Raimon
A1 Andrisano, Vincenza
A1 Loza García, María Isabel
A1 Brea Floriani, José Manuel
A1 Bartolini, Manuela
A1 Bolognesi, Maria Laura
A1 Decker, Michael
A1 Pallàs, Mercè
A1 Luque, F. Javier
A1 Muñoz Torrero, Diego
K1 Alzheimer's disease
K1 Multitarget compound
K1 Cryptic pocket
K1 SAMP8
K1 Zebrafish embryo
AB Starting from six potential hits identified in a virtual screening campaign directed to a cryptic pocket of BACE-1, at the edge of the catalytic cleft, we have synthesized and evaluated six hybrid compounds, designed to simultaneously reach BACE-1 secondary and catalytic sites and to exert additional activities of interest for Alzheimer's disease (AD). We have identified a lead compound with potent in vitro activity towards human BACE-1 and cholinesterases, moderate Aβ42 and tau antiaggregating activity, and brain permeability, which is nontoxic in neuronal cells and zebrafish embryos at concentrations above those required for the in vitro activities. This compound completely restored short- and long-term memory in a mouse model of AD (SAMP8) relative to healthy control strain SAMR1, shifted APP processing towards the non-amyloidogenic pathway, reduced tau phosphorylation, and increased the levels of synaptic proteins PSD95 and synaptophysin, thereby emerging as a promising disease-modifying, cognition-enhancing anti-AD lead
PB Elsevier
YR 2021
FD 2021-06-16
LK https://hdl.handle.net/10347/45073
UL https://hdl.handle.net/10347/45073
LA eng
NO Caterina Pont, Tiziana Ginex, Christian Griñán-Ferré, Matthias Scheiner, Alexia Mattellone, Noemí Martínez, Elsa M. Arce, Yolanda Soriano-Fernández, Marina Naldi, Angela De Simone, Marta Barenys, Jesús Gómez-Catalán, Belén Pérez, Raimon Sabate, Vincenza Andrisano, María Isabel Loza, José Brea, Manuela Bartolini, Maria Laura Bolognesi, Michael Decker, Mercè Pallàs, F. Javier Luque, Diego Muñoz-Torrero, From virtual screening hits targeting a cryptic pocket in BACE-1 to a nontoxic brain permeable multitarget anti-Alzheimer lead with disease-modifying and cognition-enhancing effects, European Journal of Medicinal Chemistry, Volume 225, 2021, 113779, ISSN 0223-5234, https://doi.org/10.1016/j.ejmech.2021.113779
NO This work was supported by Ministerio de Ciencia, Innovación y Universidades (MCIU), Agencia Estatal de Investigación (AEI) and FEDER (SAF2017-82771-R, PID2019-106285RB, CTQ2017-88446-R) and Generalitat de Catalunya (GC) (2017SGR106, 2017SGR1746). A fellowship from Ministerio de Educación, Cultura y Deporte to C.P. is gratefully acknowledged. The Consorci de Serveis Universitaris de Catalunya (CSUC) is acknowledged for providing computational resources (Molecular Recognition project). We thank Dr Ornella Di Pietro for critical reading of the manuscript. TOC graphic zebrafish embryo icon was created with BioRender.com
DS Minerva
RD 28 abr 2026