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EGCG-like non-competitive inhibitor of DYRK1A rescues cognitive defect in a down syndrome model
Jean M Delabar1, Marco Antônio G B Gomes2, Marta Fructuoso1
1Paris Brain Institute (ICM), Centre National de la Recherche Scientifique (CNRS) UMR 7225, INSERM U1127, Sorbonne Université, Hôpital de la Pitié-Salpêtrière, Paris, 75013, France.
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.
Insights
New EGCG-like molecules were synthesized to target the DYRK1A gene, which is implicated in Down syndrome (DS) and Alzheimer
Area of Science:
- Molecular Biology
- Neuroscience
- Medicinal Chemistry
Background:
- Overexpression of the DYRK1A gene on chromosome 21 is linked to cognitive impairments in Down syndrome (DS) and neurofibrillary tangle pathology in Alzheimer's and other neurodegenerative diseases.
- Epigallocatechin-3-gallate (EGCG), a green tea polyphenol, non-competitively inhibits DYRK1A activity and offers protection against DYRK1A-induced brain defects.
- Existing DYRK1A inhibitors lack the non-competitive inhibition profile of EGCG.
Purpose of the Study:
- To synthesize novel EGCG analogues with enhanced stability and potency.
- To investigate if these analogues retain EGCG's non-competitive inhibition of DYRK1A.
- To evaluate the therapeutic potential of these analogues in a Down syndrome mouse model.
Main Methods:
- Structural modifications of EGCG were performed, including replacing the ester bond with an amide bond, the oxygen ring with a methylene group, and introducing a nitrogen atom into the ring.
- The synthesized compounds were tested for their inhibitory activity and mechanism against DYRK1A.
- Biochemical and behavioral assessments were conducted in a Down syndrome mouse model using the most promising analogue.
Main Results:
- A novel EGCG-like compound was successfully synthesized, exhibiting high stability and specificity.
- The selected compound maintained the non-competitive inhibition of DYRK1A, similar to EGCG.
- This compound effectively corrected biochemical and behavioral deficits in a Down syndrome mouse model.
Conclusions:
- The synthesized EGCG analogue represents a promising therapeutic candidate for conditions associated with DYRK1A overexpression, such as Down syndrome.
- The non-competitive inhibition mechanism is preserved in the modified molecule, offering a distinct advantage over other DYRK1A inhibitors.
- Further research into these stable and specific EGCG analogues could lead to new treatments for neurodegenerative disorders.
