Virology Core

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Abstract Core 1 (Virology) The MAVDA Virology Core (MVC; Core 1) has been established to provide cell-based infection assays to evaluate the effectiveness of hit and lead compounds targeting a range of essential viral enzymatic activities as identified by MAVDA Project Leaders. Working in close collaboration with all Project Teams and Cores, the MVC will conduct early-stage dose-response studies of hit and lead antiviral compounds in cells susceptible to SARS- CoV-2 and related coronaviruses. The MVC will also determine cytotoxicity and predicted therapeutic windows for these compounds. The data provided by the MVC is essential for the drug discovery pipeline and will inform central iterative efforts to optimize promising compounds and form the basis for making go/no-go decisions for moving promising compounds forward into mechanistic and animal studies using relevant in vivo models of COVID-19. The MVC also has the added capability of selecting for and identifying resistant viral variants that may further inform modes of action for lead compounds, as well as efforts to maximize resistance barriers against viral escape from therapy. Capacity to screen additional viruses of pandemic importance, including alphaviruses and flaviviruses, will also be made available to Project Teams. The MVC will be a single entity headed by Charles M. Rice (The Rockefeller University; RU), Stephen P. Goff and Yosef Sabo (Columbia University Medical Center; CUMC) and David S. Perlin (Center for Discovery & Innovation, Hackensack Meridian Health; CDI-HMH). Their combined labs possess decades of expertise in developing and implementing cell-based assays using natural virus isolates and engineered reporter systems from dozens of viruses in the corona-, flavi-, paramyxo-, bunya-, toga-, filo-, and picorna- RNA virus families. The infrastructures of their host institutions and regulatory support for working with biosafety level 2 and 3 priority pathogens using state-of-the-art techniques with low to high-throughput capabilities will provide critical first pass and follow up pre-clinical evaluation support for compounds developed by MAVDA Projects 1-6. These efforts form a central pillar upon which compounds identified by Project teams can be rapidly and efficiently evaluated for antiviral potency and potential in vivo efficacy for a variety of viral infections while minimizing cellular toxicity.