Computer-aided discovery of synergistic drug combinations with Remdevisir for COVID-19 through mechanism-based drug repurposing and combinatorial organoid screening. [Added supplements: COVID-19 Variant Supplement, COVID-19 Variant Network]

With more than 4 million cases and over 300,000 deaths worldwide, it is critical to find an effective treatment against COVID-19 and to find it fast. Hopes for ending the pandemic largely rely on new vaccines, however the development of vaccines typically takes years and even if one is available today (which is not), its approval will take more than a year in the most optimistic scenario. Thus, the only realistic option for rapid COVID-19 treatment is drug repurposing. Drug reprofiling (repurposing) implies the use of existing drugs approved for other indications, and yet showing useful activity against SAR-CoV-2 virus. One well-known example of this strategy is remdesivir, currently the most promising treatment against COVID-19, and which was originally developed as Hepatitis C drug. Although very promising, remdesivir is still modestly efficient against COVID-19 and hence, if one could further boost its effectiveness by using it in a synergetic combination with another reprofiled drug, the pandemic might finally see the resolution. This consortium of national and international scientists wants to identify such much-needed SARS-CoV-2 inhibitor among known drugs, which then will be used either as stand-alone therapy for COVID-19 or a synergetic 'booster' for remdesivir. This team of scientists was recently awarded four COVID-19 rapid response grants to build a state-of-the-art organoid-based screening platforms established at UBC CL3 infectious disease facility, working in sync with high-resolution crystallography and artificial intelligence-enhanced molecular modeling and imaging platforms. We are ready and prepared to push forward this project even in this extremely condensed 1-year timeframe. The proposed research will generate high quality data on COVID-19 treatments shared through extensive international collaborations, will initiate critical clinical trials, and will position Canada as a world leader in the global fight against the pandemic.