THESIS OBJECTIVE. Develop PROTAC molecules for proteasome-mediated degradation of toxins internalized in host cells, and propose drug candidates for in vivo studies at the end of the thesis.

BACKGROUND AND CHALLENGES. Plant and bacterial toxins are among the most toxic natural substances, and are responsible for fatal diseases such as botulism and tetanus. Once the toxin is internalized in the target cells, immunotherapy is ineffective, and there are no curative treatments for these biomolecules. One way of achieving a major breakthrough in the development of medical countermeasures would be to target the toxin directly into the cytoplasm of host cells using PROTAC molecules. PROTACs are heterobifunctional degraders that specifically eliminate targeted proteins by hijacking the cell's ubiquitin-proteasome system. This recent therapeutic strategy represents an attractive technology for new drug discovery.

METHODOLOGY. To carry out this project, the thesis student will carry out in silico screening campaigns to identify ligands for a toxin and improve their affinity. Key validation experiments will require recombinant production of a toxin fragment, and will be carried out in E. coli. From the most promising optimized ligands, targeted libraries of PROTAC molecules directed against the toxin will be synthesized in collaboration with a team of chemists. The student will evaluate the ability of these molecules to interact with and eliminate the internalized toxin in cultured cells using different approaches, in order to propose drug candidates for in vivo studies at the end of the thesis.