DC 11: Design, synthesis and biological evaluation of RNA ligands targeting the SAM-I/IV riboswitch

PhD project description:

The SAM-I/IV riboswitch belongs to a class of riboswitches that specifically binds to S-adenosylmethionine (SAM), a cofactor used in many kinds of methylation reactions. During the development of the project, in collaboration with DC12 and 13, we aim to perform the structure-based design of new ligands specific for this riboswitch using the available crystal structures and the structures determined in WP1 as well as taking advantage of the different analogues of SAM available in the literature for other scopes in addition to the hits discovered here. We will perform the synthesis of different series of RNA binders bearing suitable physico-chemical properties for prokaryote targeting and evaluate their affinity and selectivity using fluorescence-based biochemical assays available in the laboratory (the latter will also be done for other RNA targets). To determine selectivity, we will also measure ligand binding to tRNA and double stranded DNA. The biological evaluation of the most promising compounds in vitro will then be performed during secondments at MUAS and in collaboration with DC8 and DC9. We thus expect to obtain active compounds suitable for further lead optimization but also to increase our knowledge about RNA targeting and biological function thanks to these important chemical biology tools.