Virus Inhibition by siRNA Optimized by NMR

The last two years, profoundly marked by the COVID-19 sanitary crisis, have demonstrated the difficulties to answer adequately to the emergence of novel pathogenic viruses. Today, no broad-spectrum antiviral exists similar to antibiotics targeting bacteria. Repositioning of existing molecules had limited success despite intense initial hopes. Vaccines have played a major role in fighting the pandemic and limiting the impact of the virus, however it remains insufficient to end the pandemic, due to many factors including their worldwide uneven accessibility, their intrinsic efficiency towards different variants and the complex socio-political context related to mass vaccination. There is therefore an urgent need of novel approaches to design molecules targeting viruses and in particular SARS-CoV-2. To answer this challenge, we propose a novel strategy derived from fundamental research on small interfering RNA (siRNA). This project derives from the ERC Starting Grant PARAMIR, in which novel structural biology approaches are proposed to understand the mechanism of recognition of a similar class of RNA involved in numerous diseases, especially cancer. Our approach combines the latest advances in SARS-CoV-2 virology and structural biology to propose efficient and specific molecules active towards a broad range of SARS-CoV-2 current and future variants. If successful the project will lead to a class of siRNA, with optimized specificity and stability, validated in vitro and ex-vivo in a reconstituted human airway epithelial model, and ready for testing towards pre-clinical and clinical stage. Finally, the strategy proposed here will be on a longer term applicable to multiple other pathogenic viruses.