PhD in organic chemistry (M/F) – Synthesis and biological evaluation of nucleos(t)ide analogues developed to fight against (re)emerging viruses

Population growth, global warming and mondialisation have favored the emergence and/or re-emergence of RNA viruses responsible for highly fatal viral diseases, that threaten public health and global economy. The COVID-19 pandemic crisis is the most recent example of the dramatic consequences of these viral deseases. Hemorrhagic fever viruses (HFVs), such as dengue (DENV), Lassa fever (LASV) and others, are also classified by the WHO as “high-risk disease vectors » due to their resurgent epidemic potential. To date, no specific drug has been approved for use against these HFVs. It therefore remains urgent for scientists to react by accelerating research into these high-risk pathogens, and in particular to search for therapeutic solutions to treat these diseases by pre/post-exposure prophylaxis or curative therapy.

Among the arsenal of antiviral agents available, nucleos(t)ides represent an important class, with over 30 analogues currently approved for the treatment of viral infections. The SYMBIOSE team in CEISAM laboratory (UMR CNRS 6230, Nantes) has acquired expertise in nucleoside chemistry, developing several programs for the synthesis of nucleoside derivatives through academic and industrial collaborations. As part of a national GAVO consortium, SYMBIOSE has recently developed robust synthetic strategies for the elaboration of novel 1'-C-nucleosides and 3'-C-3'-deoxy nucleos(t)ides. Several molecules studied by our virologue partners are active on specific viruses including HIV and SARS-Cov2. The aims of the thesis project are to optimize molecules with the best antiviral spectrum and to develop new synthetic strategies to access key nucleoside precursors for the development of original families of 1' or 3'-C-nucleo(t)sides.

While vaccination is an essential tool in the prevention of viral infections, and while some therapeutic research has led to significant successes, as in HIV and hepatitis treatments, there are currently no antiviral drugs against a large number of highly lethal (re)emerging viruses.  Developing the arsenal of antiviral molecules therefore remains a vital and topical challenge for the scientific and medical communities. 

Our challenges are :

• Develop robust synthetic routes to novel nucleoside analogues in a limited number of steps for potential development into new drugs.
• Develop nucleoside analogue libraries that will be taken over by the ChemBioFrance national chemical library for distribution and testing by academic virologist partners
• Identify molecules with the broadest antiviral spectrum to offer a rapid therapeutic solution in the event of emerging epidemics.
• Offer economically reasonable prophylactic or therapeutic antiviral treatment to reduce inequalities in access to care in all countries.