Midwest AViDD Center

Overall – Midwest AViDD Center ABSTRACT The Midwest Anti-Viral Drug Development (AViDD) Center was formalized as a direct response to NIAID U19 RFA RFA-AI-21-050 “Emergency Awards: AViDD Centers for Pathogens of Pandemic Concern”. The Co- PIs of the Midwest AViDD Center are Reuben Harris and Fang Li, who have deep experience in functional and

structural virology, respectively, and in leading multidisciplinary teams to successful outcomes. The majority of our center investigators were already working together in various capacities when this RFA was announced, and the RFA catalyzed the nucleation of our comprehensive multidisciplinary center focused on innovative antiviral

drug development. The primary target of the Midwest AViDD Center is SARS-CoV-2 (SARS2), with all five Projects targeting essential viral processes (two for cell entry and projects for proteolytic cleavage, nucleolytic digestion, and RNA helicase activity). We purposely selected a balance of well-established antiviral drug targets

(entry, protease), as well as less conventional targets with equally promising long-term potential (nuclease, helicase). All five Projects require integrated and highly collaborative support from five distinct service Cores for administration, screening, chemistry, structural and computational biology, and virology. A major strength of the

Midwest AViDD Center is a 3-pronged screening approach [ultra-High Throughput Screening (uHTS), DNA- Encoded Chemistry Technology (DEC-Tec), and Virtual Screening (VS)] to maximize chemical space and obtain favorable starting points for antiviral drug development. Each Project will also pursue inhibitors of the same

assigned target for an additional RNA virus of pandemic potential – the arenaviruses Lassa virus (LASV) and Machupo virus (MACV), the filovirus Ebola virus (EBOV), and the flavivirus Zika virus (ZIKV). Each Project therefore has a built-in capacity to assess inhibitor specificity throughout the course of drug development. Thus,

the overall activities of the Midwest AViDD Center are organized into two specific aims. The first aim is dedicated to research and development, where our five Projects and five Cores leverage a combination of established and innovative approaches to develop novel, high potency, and orally available inhibitors of essential viral

proteins required for pathogenesis of SARS2 and the other viruses with pandemic potential. The second is dedicated to interdisciplinary training, education, and outreach. Interdisciplinary training is vital for both addressing the current COVID-19 pandemic as well as for preparing for the next one. Education and outreach

are also essential to achieve immediate and long-term impacts. Major deliverables will therefore be novel antiviral lead compounds for further development by industry partners and, equally important, a well-trained group of antiviral researchers including next generation experts and leaders. Both deliverables will have lasting, long-term

impacts, hopefully contributing to ending the current pandemic and becoming better prepared for future viral outbreaks and stopping them before reaching pandemic levels.