The Antiviral Countermeasures Development Center (AC/DC) will target pathogens in five families of RNA viruses with significant pandemic potential, with the overarching goal to identify and develop orally bioavailable, direct acting antiviral drugs (DAAs). Specific viral targets include zoonotic and human viruses in the coronavirus, paramyxovirus, flavivirus, picornavirus, and togavirus families. The AC/DC MPIs Drs. Painter and Plemper, who will lead this effort, have demonstrated the power of their combined expertise in identifying novel antiviral chemotypes and advancing them from hit stage to clinical candidate, best exemplified by their successful joint work on molnupiravir, considered for emergency approval as the first oral therapeutic for the treatment of COVID- 19. The MPIs have assembled a team of recognized experts in the biology of the viral pathogens being targeted. Their efforts are organized into five synergistic projects supported by cutting-edge technical expertise in five AC/DC scientific cores, covering key areas of preclinical drug discovery and development. A number of the core leaders have significant experience in the development of antivirals in the pharma and biotechnology sectors. The AC/DC will achieve its overarching goal in two major objectives. Pilot studies identified two chemically distinct broad-spectrum ribonucleoside analogs and two non-nucleoside viral polymerase inhibitors with confirmed oral efficacy against one or several of the five viral families targeted, including a novel chemotype that is orally efficacious against SARS-CoV-2 in relevant animal models. Objective 1 will advance this set of four novel DAA leads through final synthetic optimization and de-risking in animal models and primary human organoids as immediate deliverables to mitigate the urgent threat to public health. Simultaneously, Objective 2 will identify additional viable hit chemotypes to expand the AC/DC's antiviral portfolio by leveraging Center expertise in reverse genetics of all viral target families, existing groundbreaking reporter virus technologies, and high-throughput screening under standard and high biocontainment conditions. Hits will be counterscreened against all center target families, molecular viral targets and mechanism of action characterized, and a potency, pharmacokinetics, and pharmacophore-driven synthetic development program launched to identify optimized leads. All data generated by the projects and cores will be evaluated Center-wide utilizing quantitative performance milestones of a defined AC/DC lead advancement cascade that governs the progression of a chemotype from hit to clinical development candidate.

Narrative The COVID-19 pandemic has called to global attention the unmitigated threat posed by emerging and re- emerging zoonotic RNA viruses to human health, societies, and the global economy. The development of next generation orally bioavailable direct-acting antivirals to prevent or mitigate disease, interrupt community transmission chains, and potentially silence a nascent pandemic is imperative. Building on extensive expertise in antiviral drug development and a panel of initial lead chemotypes, the Antiviral Countermeasures Development Center will identify and develop orally efficacious direct-acting nucleoside analog and non- nucleoside small-molecule antivirals to clinical candidate stage.