Prof. Jean-Pierre Bazureau, laureate of the Foundation Rennes1 2020 Research Award

Discovery of a molecule derived from a marine sponge, able to cope with Alzheimer's disease
Prof. Jean-Pierre Bazureau, laureate of the Foundation Rennes1 2020 Research Award

PRESS RELEASE, October 15, 2020

The Foundation Rennes1 2020 Research Award aims to recognize and highlight the work of a team of researchers at the University of Rennes 1, meeting the criteria of academic excellence and innovation in connection with the socio-economic world.

Alzheimer disease is a complex neurodegenerative disease, which gradually and insidiously affects the cognitive functions of the patients (memory, reasoning, problem solving, decision making, etc.). This pathology affects 900,000 people over the age of 65 in France, of whom 2 out of 3 are women. In 2015, there are approximately 48 million people worldwide suffering from this disease and to date no molecule is really effective.

In terms of new molecules for the pharmaceutical industry, the ocean and more particularly marine sponges, have offered serendipitous innovation opportunities to two research chemists from Rennes Institute of Chemical Sciences (University of Rennes 1 / CNRS / ENSCR/ INSA), Prof. Jean-Pierre Bazureau and Dr François Carreaux.

Leucettamine B, a molecule present in the Leucetta microraphis sponge, was the source of inspiration for the molecular design of a new therapeutic family named leucettines. This therapeutic innovative work, developed since 2006 in partnership with Dr Laurent Meijer, a biologist specialized in protein kinase research and co-founder of the biotech Perha Pharmaceuticals, has shown that leucettines offer excellent regulation properties on the "dyrk1A enzyme " connected to Down syndrome and Alzheimer disease. In humankind, 518 kinases are proteins that regulate cell life and when they are overactivated, this induces pathologies. Among these, "dyrk1a" occupies a special place because it is found in abnormal quantities on the 3 chromosomes of trisomy, and this overactivated "dyrk1A" is also present in the brain of people suffering from Alzheimer's disease. The injection of leucettines on "model of trisomy" mice shows a clear improvement in cognitive behavior and a stabilization of memory. The encouraging current results issued from this academic and industrial collaboration open up promising prospects for the selection of a short-term drug candidate for further clinical trials.
 

Learn more


 

References

  • Inhibition of DYRK1A proteolysis modifies its kinase specificity and rescues Alzheimer phenotype in APP/PS1 mice. Souchet B., Audrain M., Billard J-M., Dairou J., Fol R., Orefice N., Tada S., Dufayet G., Alves S., Potier B., Dutar P., Limanton E., Carreaux F., Bazureau J-P., Meijer L., Janel N., Braudeau J., Cartier N. Acta Neuropathologica Communications 2019, 7, article: 46(2019). https://doi.org/10.1186/s40478-019-0678-6.
     
  • Correction of cognitive deficits in mouse models of Down syndrome by pharmacological inhibitor of DYRK1A. T. L. Nguyen, A. Duchon, A. Manousopoulou, N. Loaëc, B. Villiers, G. Pani, L. Harsan, E. Limanton, J-P. Bazureau, F. Carreaux, S. D. Garbis, L. Meijer, Y. Herault. Disease Models & Mechanisms 2018, 11, dmm035634. doi: 10.1242/dmm.035634.
     
  • Leucettine L41, a DYRK1A inhibitor, prevents memory impairments and neurotoxicity induced by icv administration of aggregated Aβ25-35 in mice. G. Naert, V. Ferré, J. Meunier, E. Keller, S. Malmström, L. Givalois, F. Carreaux, J-P. Bazureau, T. Maurice*. Eur Neuropsychopharmacology 2015, 25, 2170-218.
     
  • CLK/DYRK kinases inhibitor Leucettine L41 induces mTOR-dependent autophagy. Implication for Alzheimers’ disease. X. Fant, E. Durieu, G. Chicanne, B. Payrastre, D. Sbrissa, A. Shisheva, E. Limanton, F. Carreaux, J-P. Bazureau, L. Meijer. Molecular Pharmacology 2014, 85, 441-450.
     
  • Chemical synthesis and biological validation of immobilized protein kinase inhibitor Leucettine. G. Burgy, T. Tahtouh, E. Durieu, B. Josselin-Foll, E. Limanton, L. Meijer, F. Carreaux, J-P. Bazureau. Eur J. Med.Chem. 2013, 62, 728-737.
     
  • Selectivity, co-crystal structures and neuroprotective properties of Leucettines, a family of protein kinase inhibitors derived from the marine sponge alkaloid Leucettamine B. T. Tahtouh, O. Federov, M. Soundararajan, G. Burgy, E. Durieu, O. Lozach, C. Cochet, R.S. Schmid, D.C. Lo, F. Delhommel, A. E. Oberholzer, L. H. Pearl, F. Carreaux, J-P. Bazureau, S. Knapp, L. Meijer. ACS J. Med. Chem. 2012, 55(21), 9312-9330.
     
  • Leucettines, a class of potent CLK and DYRK kinases inhibitors derived from the marine sponge leucettamine B. Modulation of alternative RNA splicing. M. Debdab, F. Carreaux, S. Renault, M. Soundararajan, O. Federov, O. Lozach, L. Babault, B. Baratte, Y. Ogawa, M. Hagiwara, A. Einsenreich, U. Rauch, S. Knapp, L. Meijer, J-P. Bazureau. ACS J. Med. Chem. 2011, 54, 4172-4186.
     
  • Imidazolone derivatives, preparation method thereof and biological use of same. J-P. Bazureau, F. Carreaux, S. Renault, L. Meijer, O. Lozach. European Patent EP 2 185 547 B1, dépôt: 08838929.1, publication 19.07.2017.
     
  • Imidazolone derivatives, preparation method thereof and biological use of same. J-P. Bazureau, F. Carreaux, S. Renault, L. Meijer, O. Lozach. Brevet WO 2009/05032 (A2) du 23 Avril 2009. Demande PCT/FR 2008/001152 du 01/10/2008. Extensions: FR 2919608 (A1), FR 2919608 (B2), US 2010/216855 (A1), US 8563588 (B2), RU 2010/107262 (A), RU 2491283 (C2), MX 2010/001170 (A), KR 2010/0051698 (A), JP 2010/535180 (A), EP 2185547 (A2), CN 101784542 (A), CN 101784542 (B), CA 2694377 (A1).

Contacts

  • Jean-Pierre Bazureau - jean-pierre [dot] bazureauatuniv-rennes1 [dot] fr
    Univ Rennes, CNRS, ISCR-6226, F-35000 Rennes, France
     
  • Estelle Monthorin - estelle [dot] monthorinatuniv-rennes1 [dot] fr
    Univ Rennes, Fondation Rennes1, 2 Rue du Thabor, F-35000 Rennes, France

 

Published : 2020-10-19