SUMMARY Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2 (SARS- CoV-2), exploded into a global pandemic in late 2019 causing significant loss of life, pronounced economic disruption and major long-term medical impacts which are still being characterized. The current COVID19 pandemic highlighted our severe lack of preparedness and, despite an effective vaccine being developed in record time, the continued need for efficacious antiviral drugs to quell the morbidity and mortality associated with infection became evident. Despite an accelerated push to identify and bring forward anti-viral medicines, few made it to the clinic in time to prevent the approximately 700,000 deaths observed in the United States and several million across the globe. Moreover, many emerging and re-emerging viral diseases with pandemic potential have been identified which could bring similar or excess morbidity and mortality as COVID19 in a future pandemic event. This pandemic highlights the need to get ahead of viruses with pandemic potential to be ready for the next outbreak. As such, the goal of this proposal is to identify novel, direct-acting antivirals. The broad, long-range objectives of the Animal and Organoid Model Core (Core D) are to develop/employ organoid and animal models for testing of selected candidate anti-viral compounds generated in projects 1-6 of this U19 application. The Animal and Organoid Model Core will work in conjunction with the project leaders (projects 1-6), HTS core (Core A), medicinal chemistry core (Core B) and the absorption, distribution, metabolism, excretion and toxicity (ADMET)/formulation core (Core C) to identify, modify and formulate candidate hits for in vivo testing in the animal models. The primary goal will be the development of potent, orally bioavailable direct acting antiviral compounds against specific Coronavirus, Flavivirus and Bunyavirus targets described within this proposal.