Project 1 of the AC/DC focuses on highly pathogenic human beta-coronaviruses with the overarching objective to advance a novel nucleoside analog inhibitor class that we recently reported (Sourimant et al. Science, 2022) and at least one mechanistically and structurally distinct alternative towards formal development. In a collaborative effort between the Plemper laboratory at Georgia State University and the Martinez laboratory at Texas Biomed, project 1 will harness our demonstrated strengths in high-throughput screen development, mechanistic and potency characterization of lead candidates, synthetic lead optimization, and pharmacokinetic profiling to reach this goal. Efficacy of emerging drug candidates will be tested in relevant animal models that we have established including the SARS-CoV-2 ferret upper respiratory disease and transmission model and the Roborovski dwarf hamster model for acute respiratory failure of patients at elevated risk of developing life-threatening acute COVID-19. Synergizing closely with the Scientific Cores and projects 2 and 4 of the AC/DC, project 1 will deliver next-generation therapeutic candidates to expand our arsenal for the treatment of SARS-C0V-2 infection and prepare against spillover of other zoonotic beta-coronaviruses with pandemic potential into the human population.
