Development of an Oral Pan-Coronavirus Drug Cocktail

ABSTRACT This R01 comprises a collaboration between scientists in the US and Belgium that seeks to develop synergistic antiviral drug combinations that keep pace with the evolution of the SARS-CoV-2/COVID-19 pandemic and future outbreaks of related coronaviruses. We will exploit i) the principles of synergistic activity that arise with drug combinations and ii) novel mathematical approaches to optimize human dosing for treating emerging and re-emerging coronaviruses with pandemic potential. We will identify combinations of drugs that i) target conserved cellular factors that support virus infection, and/or ii) target viral enzymes that are essential for viral replication, to develop novel antiviral drug combinations against multiple coronaviruses (i.e., a pan-family drug cocktail). Based on our previous work, mathematical modeling approaches will be used to i) identify drug combinations with synergistic antiviral action, ii) prioritize drug combinations and dosing strategies for testing in rodent models of virus infection and disease, and iii) predict in vivo efficacy in humans with various dosing strategies. Our research plan provides a proactive approach for global pandemic response and preparedness, with deliverables consisting of i) combinations of compounds that confer potent, synergistic suppression of multiple coronaviruses and have sufficiently high and durable plasma and tissue concentrations and ii) publicly available harmonized clinical trial designs that will allow for efficient testing of multiple agents in parallel at the inception of new epidemics. As the approach is applicable to any virus family, the project portends global impact by improving protection of the general population against existing viral threats, enhancing preparedness and response for future viral outbreaks, and offering immediately testable and deployable oral drug combinations that fill the time void between virus identification and development and deployment of viral sequence-specific vaccines, antibodies, and drugs.