C-glycosides analogues of the okadaic acid central fragment exert neuroprotection via restoration of PP2A-phosphatase activity: A rational design of potential drugs for Alzheimer's disease targeting tauopathies

Published: 31 October 2022| Version 1 | DOI: 10.17632/kv9vr2jxbm.1
, Isaac Bravo,


These data illustrates the capacitity of a family of C-glycosides to enhance and activate protein phosphatase 2A (PP2A). This enzyme is an important Ser/Thr phosphatase that participates in the regulation of multiple cellular processes, and its deficient activity of PP2A has been involved in the etiology of various diseases. The C-glycosides presented in this set of data are analogues to the central fragment of the toxin okadaic acid, which selectively inhibits PP2A. Chemical design aimed to turn the pharmalogical activity in a PP2A-activating profile. In order to probe our hypothesis, these compounds were tested in pharmacological models of Alzheimer's disease (AD). Depression of PP2A has been widely corroborated in AD, where the resulting manifestation is the hyperphosphorylation of several PP2A substrates, such as tau protein. Indeed, one of the main histopathological features of AD are neurofibrillary tangles, formed by hyperphosphorylated tau protein. Therefore, data herein deposited show: 1) recovery of phosphatase activity by the described compounds in a scenario of PP2A depression defined by administration of either okadaic acid or cytostatin (a milder PP2A inhibitor but much more selective), monitored by the pNPP method: files "pNPP vs..." 2) protection of neuroblatoma cultures and cortical neurons exerted by compounds in presence of several toxic stimuli related to neurodegeneration (okadaic acid, cytostatin, rotenone plus oligomycin A or glutamate) measured by MTT method: files "Protection vs ..." 3) effect of the best PP2A-activating compound (10) on the PP2A activity of two diferent trimeric complexes, namely B55alpha and B56alfa, measured by the malachite green method: file "Malachite of 10 vs OA by Arribas et al" 4) effect of 10 on the expression of PP2A phosphoprotein substrates in presence of okadaic acid: files "WB of ..." 5) computational docking of compound 10 at its binding site in PP2A-AC dimer: files "Docking of most stable 10 at PP2A" 6) study of the CNS penetration of compound 10 by PAMPA: file "PAMPA of 10 by Arribas et al" 7) in vivo studies of the effect of 10 on the memory deficit exacerbated by LPS in mice, measured by the object recognition test: file "ORT of 10 vs LPS by Arribas et al" These promising experimental data, centered on profiling the lead compound ITH12711 (10)(X ray data also deposited as cif file and crystal structure report", would validate our rational approach to design new PP2A-activating drugs based on OA central fragment.



Universidad Rey Juan Carlos Facultad de Ciencias de la Salud, Universidad Autonoma de Madrid


Pharmaceutical Chemistry