Orally Bioavailable Antiviral Drugs with Broad Pandemic Virus Activity

Abstract Three years ago, we proposed to apply our novel lipid chemistry platform to create highly potent, orally bioavailable compounds directed at SARS CoV2. By conjugating remdesivir monophosphate to lipophilic hydrocarbon side chains, we have developed a series of compounds that exhibit potent anti-SARS CoV2 activity. These compounds are well tolerated and highly bioavailable in mice and produce sustained, high-level intracellular exposure to remdesivir triphosphate. In proof-of-concept studies we demonstrated once-daily oral dosing of our compounds was superior to obeldesivir in a murine SARS CoV2 model infection. Because of their potency, favorable tolerability and pharmacokinetic properties, we evaluated their antiviral activity against several additional emerging viral pathogens. We have demonstrated antiviral activity at orally achievable levels of drug against a diverse set of pathogens with pandemic potential including Ebola, Marburg, Nipah, Hendra, Yellow Fever and Dengue viruses. Although we are not proposing to study these non-pandemic viruses in this application, further supporting their broad spectrum, our compounds were also highly active against measles and mumps virus. Recent studies extended the proof-of-concept to dengue virus by demonstrating full protection of ADE-enhanced immunodeficient mice from a lethal dengue virus challenge. In this renewal application, we propose to determine whether we can further enhance oral bioavailability of the compound series by utilizing formulations that favor micellar formation of prodrug in the gut. We wish to further explore structure-function relationships to determine whether we can create compounds with more potent antiviral activity and/or enhanced pharmacological properties. Finally, with the optimized compounds, we wish to conduct validation studies against additional pathogens of pandemic potential. We believe that these compounds have the potential to be efficacious when delivered orally once daily against several viral pathogens of medical importance including dengue and respiratory syncytial virus and that they could prove to be critically useful in early use in early use against several pathogens with significant pandemic potential.