Project Summary/Abstract The current outbreak of COVID-19 has had devastating global effects on morbidity and mortality. Currently no vaccine is available and no therapeutic with efficacy against SARS-CoV-2019 have been fully approved by the FDA. Remdesivir, an intravenous drug which inhibits the viral RNA polymerase enzyme, has received an EUA designation by the US FDA. A prodrug of N4-hydroxy-cytidine has recently entered Phase 1 trials. Our goal is to synthesize COVID-19 antivirals that inhibit the viral RNA polymerase and can be used orally or intramuscularly with a special focus on delivering maximal amounts of drug to the lungs. We will synthesize prodrugs of remdesivir and other nucleosides with anti-coronavirus activity using an innovative approach that involves converting them to lipid analogs. Some compounds will focus on oral delivery and others on intramuscular administration. The compounds will be screened in vitro against nonpathogenic and pathogenic coronaviruses including SARS-CoV-2 and their activity compared with the unmodified parent nucleosides. Their pharmacokinetics and toxicity of the most active antivirals will be studied in rats. The active antivirals will be evaluated for exposure to lung versus their unmodified nucleosides. Finally, the clinical and antiviral activity of the most promising compounds will be evaluated in the Syrian Golden hamster model of coronavirus disease.