Abdelhakim Ouarti PhD defense

Mr. Abdelhakim Ouarti will defend his thesis entitled
Broad-spectrum antiviral nucleoside delivery device using mono and multivalent galactosidic systems.

March 07, 2022
2 p.m., Amphitheater A4
Thesis carried out under the supervision of Dr. Florian Gallier and the direction of Prof. Nadege Lubin-Germain.
Members of the jury: Prof. Marie-Christine Scherrmann, Dr. Stéphane Guillarme, Prof. Joanne Xie and Prof. Jose Kovensky.

We have been engaged for a few years in the synthesis of C-nucleosides relying on an original methodology developed in the laboratory, and their biological applications especially vectorization. These compounds possess interesting biological activities (antitumoral and broad-spectrum antiviral). However, these activities still requires improvement. Different pathways are possible: functional modulation, prodrug development and the use of a vectorization and targeting device. These three axes are currently being developed in the laboratory. This last axis began with a first thesis and this first work concerned the use of peptides as anchor points in hepatocyte’s membranes. We have now tackled the next step, including the development of mono and multivalent glycosidic systems to enable selective addressing of C-nucleosides to asialoglycoprotein receptors, especially overexpressed on hepatocytes. The active molecule that is used and have been developed in the laboratory, SRO-91, has been the subject of a recent methodological development, using different sources of azides, commercial or synthetic, for the key step of the heterocycle construction. These new access routes allowed us to obtain the desired C-nucleoside with improved yield, less steps and also to have access to interesting intermediates. Through this thesis, we have been able to synthesize monovalent conjugates C-Gal/SRO-91, in order to study the vectorization and stability of the links between the addresser and the active molecule. Subsequently, based on this synthetic methodology of monovalents conjugates, we have synthesized a trivalent conjugate C-Gal/SRO-91 1:3. This one would allow for a higher drug load, at the expense of a loss of affinity towards asialoglycoprotein receptors. In addition, we have also managed to obtain a trivalent conjugate C-Gal / SRO-91 3:1, with 3 galactosidic units, allowing for an optimal affinity with the receptors.