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Principal Investigator: GARTH POWIS
Organization: SANFORD BURNHAM PREBYS MEDICAL DISCOVERY INSTITUTE
Fiscal Year: 2020
Award: $487,500
Funding agency: National Cancer Institute
The scientific community has mobilized around the novel coronavirus, SARS-CoV-2 which causes the pneumonia like disease named COVID-19. This virus has impacted over 210 countries and territories and almost 1.5 million people worldwide since December 2019, according to the Coronavirus Disease (COVID19) Situation Dashboard by the World Health Organization. The current research efforts across the globe center on understanding the disease, and importantly developing therapeutics and vaccines. There are currently no FDA approved drugs or vaccines for CoVs, yet three clinical stage or approved compounds have shown some promise: Remdesivir (Gilead), Favipiravir (Fujifilm), and Hydroxychloroquine (off patent). However, finding additional agents that can be used in a cocktail therapy, that may potentiate the activities of these clinical stage compounds, mitigate any potential adverse effects by allowing for lower dosing, and diminish chances of resistance development, will be an important therapeutic strategy for antiviral treatment. Thus, the identification of effective antivirals that synergize with these compounds to limit SARS-CoV-2 replication and disease represents an urgent public health necessity. We have recently completed a screen of the novel ReFRAME (Repurposing, Focused Rescue, and Accelerated MedChem) drug repositioning collection, to identify inhibitors of SARS-CoV-2 replication, and have validated over 30 clinical stage molecules that may function as SARS-CoV2 antivirals (manuscript in preparation). While these compounds function as single agents, due to the many advantages provided by combination therapy, including the potential to overcome suboptimal efficacy of individual drugs, we now propose to execute three screens in the presence of IC20 concentrations of Remdesivir, Favipiravir, or Hydroxychloroquine to identify known drugs that synergize with each of these advanced clinical candidates. Following validation of screen hits, we will then test drugs combinations with an additional clinical stage compounds (Remdesivir, Favipiravir, or Hydroxychloroquine) to identify 3 drug cocktails displaying maximal synergistic activity. By leveraging the prior investments in medicinal chemistry, pharmacology, and toxicology of the ReFRAME library, drug cocktails inhibiting SARS-CoV-2 infection will be able to be moved quickly into clinical trials to address this immediate public health emergency.
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