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Open AccessArticle

Meridianins and Lignarenone B as Potential GSK3β Inhibitors and Inductors of Structural Neuronal Plasticity

1
Department of Evolutionary Biology, Ecology and Environmental Sciences, Faculty of Biology and Biodiversity Research Institute (IRBio), Universitat de Barcelona, 08028 Barcelona, Catalonia, Spain
2
Mind the Byte S.L., 08007 Barcelona, Catalonia, Spain
3
Departament de Biomedicina, Facultat de Medicina i Ciències de la Salut, Institut de Neurociències, Universitat de Barcelona, 08036 Barcelona, Spain
4
Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), 08036 Barcelona, Spain
5
Centro de Investigación Biomédica en Red sobre Enfermedades Neurodegenerativas (CIBERNED), 28031 Madrid, Spain
6
Production and Validation Center of Advanced Therapies (Creatio), Faculty of Medicine and Health Science, University of Barcelona, 08036 Barcelona, Spain
7
Molomics, 08028 Barcelona, Spain
*
Authors to whom correspondence should be addressed.
Biomolecules 2020, 10(4), 639; https://doi.org/10.3390/biom10040639
Received: 11 March 2020 / Revised: 7 April 2020 / Accepted: 17 April 2020 / Published: 21 April 2020
(This article belongs to the Special Issue Marine-Derived Biomolecules)
Glycogen Synthase Kinase 3 (GSK3) is an essential protein, with a relevant role in many diseases such as diabetes, cancer and neurodegenerative disorders. Particularly, the isoform GSK3β is related to pathologies such as Alzheimer’s disease (AD). This enzyme constitutes a very interesting target for the discovery and/or design of new therapeutic agents against AD due to its relation to the hyperphosphorylation of the microtubule-associated protein tau (MAPT), and therefore, its contribution to neurofibrillary tangles (NFT) formation. An in silico target profiling study identified two marine molecular families, the indole alkaloids meridianins from the tunicate genus Aplidium, and lignarenones, the secondary metabolites of the shelled cephalaspidean mollusc Scaphander lignarius, as possible GSK3β inhibitors. The analysis of the surface of GSK3β, aimed to find possible binding regions, and the subsequent in silico binding studies revealed that both marine molecular families can act over the ATP and/or substrate binding regions. The predicted inhibitory potential of the molecules from these two chemical families was experimentally validated in vitro by showing a ~50% of increased Ser9 phosphorylation levels of the GSK3β protein. Furthermore, we determined that molecules from both molecular families potentiate structural neuronal plasticity in vitro. These results allow us to suggest that meridianins and lignarenone B could be used as possible therapeutic candidates for the treatment of GSK3β involved pathologies, such as AD. View Full-Text
Keywords: Computer-aided drug design; Alzheimer’s disease; marine natural products; neural plasticity; Aplidium tunicates; Scaphander molluscs Computer-aided drug design; Alzheimer’s disease; marine natural products; neural plasticity; Aplidium tunicates; Scaphander molluscs
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Llorach-Pares, L.; Rodriguez-Urgelles, E.; Nonell-Canals, A.; Alberch, J.; Avila, C.; Sanchez-Martinez, M.; Giralt, A. Meridianins and Lignarenone B as Potential GSK3β Inhibitors and Inductors of Structural Neuronal Plasticity. Biomolecules 2020, 10, 639.

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