Dans le cadre des séminaires « duos de choc », nous avons le plaisir de vous annoncer le séminaire de :

Batoul MAHCENE et Emmanuelle BRAUD

« Study of Stable SAM Analogs as promising scaffold for RNA methylation inhibition »

RNA methylation is the most abundant post-transcriptional modification, it plays a crucial role in gene regulation. Recently, RNA methyltransferase (MTase), which catalyze RNA methylation using S-AdenosylMethionine as a cofactor, have been associated with various human diseases. Thus, the development of molecules to study and modulate their activities is of great interest. In this context, our study focuses on the development of new SAM analog harboring a squarate motif, mimicking the α amino acid moiety of the methionine part. METTL3/METTL14 WTAP and METTL16, two MTase responsible for N6-methyladenosine (m6A) deposition on mRNA and snRNA respectively, were used as an in vitro model to assess the functionality of our stable SAM analogs. Based on biochemical assays using differents SAM analogs and both enzymes, no transfer of functional group on N6-adenosine was observed. However, all SAM analogs displayed significant inhibition of MTase 3/14 WTAP. Seven out of 10 analogs displayed specificity towards METTL3/14 WTAP and did not affect METTL16 even at high concentration. The remaining three SAM analogs also demonstrated inhibitory effects on METTL16 at higher concentrations. Molecular docking suggests a mechanism for METL3/14/WTAP inhibition. Such novel SAM analog based on the presence of a squarate as a bioisoster of the α amino acid moiety appear as promising starting points for the development of specific METTL3/14 inhibitors.

Le comité CiTAnim : Louise Marie Balivet, Magali Blaud, Etienne Brachet, Nathalie Chamond, Elisa Frezza, Florian Gentelet, Gilles Phan, Alexandre Potfer, Emmanuel Roulland, François-Xavier Theillet, Marlène Vayssières.