2. Academic Validation
  3. 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

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

  • Eur J Med Chem. 2023 May 5;251:115245. doi: 10.1016/j.ejmech.2023.115245.
Raquel L Arribas 1,  Lucía Viejo 2,  Isaac Bravo 3,  Minerva Martínez 4,  Eva Ramos 5,  Alejandro Romero 5,  Eva M García-Frutos 6,  Veerle Janssens 7,  Carmen Montiel 4,  Cristóbal de Los Ríos 8
Affiliations

Affiliations

  • 1 Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, 28029, Madrid, Spain; Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, 28922, Alcorcón, Spain.
  • 2 Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, 28029, Madrid, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006, Madrid, Spain.
  • 3 Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006, Madrid, Spain; Instituto de Ciencia de Materiales de Madrid, Consejo Superior de Investigaciones Científicas, 28049, Madrid, Spain.
  • 4 Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, 28029, Madrid, Spain.
  • 5 Departamento de Farmacología y Toxicología, Facultad de Veterinaria, Universidad Complutense, 28040, Madrid, Spain.
  • 6 Instituto de Ciencia de Materiales de Madrid, Consejo Superior de Investigaciones Científicas, 28049, Madrid, Spain; Universidad de Alcalá, Departamento de Química Orgánica y Química Inorgánica, Ctra. Madrid-Barcelona Km.33,600, 28871, Alcalá de Henares, Madrid, Spain.
  • 7 Department of Cellular & Molecular Medicine, Laboratory of Protein Phosphorylation and Proteomics, KU Leuven, B-3000, Leuven, Belgium; LBI (KU Leuven Brain Institute), B-3000, Leuven, Belgium.
  • 8 Instituto-Fundación Teófilo Hernando, Universidad Autónoma de Madrid, 28029, Madrid, Spain; Departamento de Ciencias Básicas de la Salud, Universidad Rey Juan Carlos, 28922, Alcorcón, Spain; Instituto de Investigación Sanitaria, Hospital Universitario de la Princesa, C/ Diego de León, 62, 28006, Madrid, Spain. Electronic address: cristobal.delosrios@inv.uam.es.
PMID: 36905916 DOI: 10.1016/j.ejmech.2023.115245
Abstract

Protein Phosphatase 2A (PP2A) is an important Ser/Thr Phosphatase that participates in the regulation of multiple cellular processes. This implies that any deficient activity of PP2A is the responsible of severe pathologies. For instance, one of the main histopathological features of Alzheimer's disease is neurofibrillary tangles, which are mainly comprised by hyperphosphorylated forms of Tau Protein. This altered rate of tau phosphorylation has been correlated with PP2A depression AD patients. With the goal of preventing PP2A inactivation in neurodegeneration scenarios, we have aimed to design, synthesize and evaluate new ligands of PP2A capable of preventing its inhibition. To achieve this goal, the new PP2A ligands present structural similarities with the central fragment C19-C27 of the well-established PP2A inhibitor okadaic acid (OA). Indeed, this central moiety of OA does not exert inhibitory actions. Hence, these compounds lack PP2A-inhibiting structural motifs but, in contrast, compete with PP2A inhibitors, thus recovering Phosphatase activity. Proving this hypothesis, most compounds showed a good neuroprotective profile in neurodegeneration models related to PP2A impairment, highlighting derivative 10, named ITH12711, as the most promising one. This compound (1) restored in vitro and cellular PP2A catalytic activity, measured on a phospho-peptide substrate and by western-blot analyses, (2) proved good brain penetration measured by PAMPA, and (3) prevented LPS-induced memory impairment of mice in the object recognition test. Thus, the promising outcomes of the compound 10 validate our rational approach to design new PP2A-activating drugs based on OA central fragment.

Keywords

Alzheimer's disease; Neuroprotection; Okadaic acid; PP2A-activating drug (PAD); Protein phosphatase 2A (PP2A); Tauopathies.

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