SARS-CoV-2 continues to cause severe morbidity and mortality in the current pandemic and future RNA virus pandemics are inevitable. Clinical-trial-ready antivirals are lacking for all RNA viruses of pandemic potential. It is imperative that the world have access to an arsenal of compounds ready to be deployed into clinical trials at the earliest stages of future pandemics. Beyond coronaviruses; flaviviruses and picornaviruses have caused frequent and ongoing epidemics around the world and there are currently no effective therapeutics available. These viral families have proven to be major threats to the human population and novel IND-ready therapeutics will be critical for our future pandemic preparedness. The ASAP AViDD Center is dedicated to the development of novel chemical matter with antiviral activity against these three viral families. The focus on targets refractory to antiviral resistance by Project 1: Antiviral Targeting to Suppress Drug Resistance and the Target Enabling Packages (TEPs) developed by Project 2: Target Enablement are highly innovative approaches that will allow the ASAP consortium to efficiently develop novel antivirals with the potential for sustained clinical success. The Antiviral Efficacy and Resistance Core plays an essential role in the ASAP Center, firstly as the primary site for in vitro screening and primary cell models, with support from Johan Neyts {KU Leuven) as a secondary in vitro screening laboratory. We will also perform comprehensive in vitro and in vivo antiviral resistance analysis and drug combination studies. Finally, we will work closely with Projects 1-6, the NIAID, and industry partners to select leads to move into in vivo analysis and determine the therapeutic efficacy of antiviral leads against these three viral families in advanced animal models of viral infection. We have assembled a team of investigators in our core with decades of experience in cell culture and advanced animal models for the analysis of antiviral countermeasures against the target viral families. A major goal of the ASAP Center is the identification and development of 3 oral antiviral drug candidates with suitable safety profiles for broad use in the outpatient setting. We have placed an emphasis on the identification of novel antiviral targets using advanced resistance-refractory target selection, Al-based fragment-based screening, structural enablement of these targets, and a comprehensive efficacy and resistance analysis. The Antiviral Efficacy and Resistance Core will be integrated into the ASAP platform by working with the consortium, the NIAID, and industry partners to select 45-50 of our top antiviral leads to test in our advanced animal models of viral infection. We will then advance up to 15 advanced leads into comprehensive in vivo efficacy analysis, and finally select 3 leads to move into in vivo resistance mutation analysis and drug combination studies using well-established methods in our laboratories. Project S...