2. Academic Validation
  3. EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model

EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model

  • Eur J Med Chem. 2024 Feb 5:265:116098. doi: 10.1016/j.ejmech.2023.116098.
Jean M Delabar 1,  Marco Antônio G B Gomes 2,  Marta Fructuoso 3,  Nadège Sarrazin 3,  Nicolas George 2,  Nadia Fleary-Roberts 2,  Hua Sun 4,  Linh Chi Bui 5,  Fernando Rodrigues-Lima 5,  Nathalie Janel 6,  Julien Dairou 7,  Edmilson J Maria 8,  Robert H Dodd 2,  Kevin Cariou 9,  Marie-Claude Potier 10
Affiliations

Affiliations

  • 1 Paris Brain Institute (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, 75013, France. Electronic address: [email protected].
  • 2 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, Gif-sur-Yvette, France.
  • 3 Paris Brain Institute (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, 75013, France.
  • 4 China International Science and Technology Cooperation Base of Food Nutrition/Safety and Medicinal Chemistry, College of Biotechnology, Tianjin University of Science & Technology, Tianjin, 300457, China.
  • 5 Université Paris Cité, CNRS, Unité de Biologie Fonctionnelle et Adaptative, F-75013 Paris, France.
  • 6 Team Degenerative Process, Stress and Aging, Unité de Biologie Fonctionnelle et Adaptative, CNRS, Université Paris Cité, F-75013 Paris, France.
  • 7 Université Paris cité, CNRS, Laboratoire de Chimie et de Biochimie Pharmacologiques et Toxicologiques, 45 rue des Saints Pères, F-75006 Paris, France.
  • 8 Laboratório de Ciências Químicas, Centro de Ciências e Tecnologia, Universidade Estadual do Norte Fluminense-Darcy Ribeiro, Av. Alberto Lamego, 2000-Parque Califórnia, 28013-602, Campos dos Goytacazes/RJ, Brazil.
  • 9 Université Paris-Saclay, CNRS, Institut de Chimie des Substances Naturelles, UPR 2301, Gif-sur-Yvette, France; current address: Chimie ParisTech, PSL University, CNRS, Institute of Chemistry for Life and Health Sciences, Laboratory for Inorganic Chemical Biology, 75005 Paris, France. Electronic address: [email protected].
  • 10 Paris Brain Institute (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, 75013, France. Electronic address: [email protected].
PMID: 38171148 DOI: 10.1016/j.ejmech.2023.116098
Abstract

Overexpression of the chromosome 21 DYRK1A gene induces morphological defects and cognitive impairments in individuals with Down syndrome (DS) and in DS mice models. Aging neurons of specific brain regions of patients with Alzheimer's disease, DS and Pick's disease have increased DYRK1A immunoreactivity suggesting a possible association of DYRK1A with neurofibrillary tangle pathology. Epigallocatechin-3-gallate (EGCG) displays appreciable inhibition of DYRK1A activity and, contrary to all other published inhibitors, EGCG is a non-competitive inhibitor of DYRK1A. Prenatal exposure to green tea Polyphenols containing EGCG protects from brain defects induced by overexpression of DYRK1A. In order to produce more robust and possibly more active analogues of the natural compound EGCG, here we synthetized new EGCG-like molecules with several structural modifications to the EGCG skeleton. We replaced the ester boun of EGCG with a more resistant amide bond. We also replaced the oxygen ring by a methylene group. And finally, we positioned a nitrogen atom within this ring. The selected compound was shown to maintain the non-competitive property of EGCG and to correct biochemical and behavioral defects present in a DS mouse model. In addition it showed high stability and specificity.

Keywords

Kinase inhibitors; Tetrahydroisoquinoline; catechine derivatives.

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