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Title: Structure-Based Virtual Screening and in vitro and in vivo Analyses Revealed Potent Methyltransferase G9a Inhibitors as Prospective Anti-Alzheimer's Agents
Author: Bellver-Sanchis, Aina
Bhanwar Singh Choudhary
Companys Alemany, Júlia
Ávila-López, Pedro A.
Martínez Rodríguez, Antón Leandro
Brea Floriani, Jose Manuel
Malik, Ruchi
Pallàs i Llibería, Mercè, 1964-
Pérez, Belén
Griñán Ferré, Christian
Keywords: Malaltia d'Alzheimer
Alzheimer's disease
Issue Date: 1-Dec-2022
Publisher: Wiley-VCH
Abstract: G9a is a lysine methyltransferase able to di-methylate lysine 9 of histone H3, promoting the repression of genes involved in learning and memory. Novel strategies based on synthesizing epigenetic drugs could regulate gene expression through histone post-translational modifications and effectively treat neurodegenerative diseases, like Alzheimer's disease (AD). Here, potential G9a inhibitors were identified using a structure-based virtual screening against G9a, followed by in vitro and in vivo screenings. First, screening methods with the AD transgenic Caenorhabditis elegans strain CL2006, showed that the toxicity/function range was safe and recovered age-dependent paralysis. Likewise, we demonstrated that the best candidates direct target G9a by reducing H3 K9me2 in the CL2006 strain. Further characterization of these compounds involved the assessment of the blood-brain barrier-permeability and impact on amyloid-β aggregation, showing promising results. Thus, we present a G9a inhibitor candidate, F, with a novel and potent structure, providing both leads in G9a inhibitor design and demonstrating their participation in reducing AD pathology. Keywords: Alzheimer's disease; G9a methyltransferase; amyloid-β; epigenetics; structure based virtual screening.
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It is part of: ChemMedChem, 2022
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ISSN: 1860-7179
Appears in Collections:Articles publicats en revistes (Farmacologia, Toxicologia i Química Terapèutica)

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