Anti-CoV: Full-cycle high-throughput infection screen to identify clinical compounds with high repurposing potential against COVID-19

The ongoing human coronavirus (HCoV) pandemic and the associated COVID-19 disease caused by SARS-CoV-2 dramatically impact individuals and societies, putting the world at disruptive risk, and democracy under enormous stress. Rapid progress in identifying anti-viral compounds for human use is urgently needed to limit the impact of the crisis, and prepare societies against recurring SARS-CoV-2, and other viral outbreaks that can be even more devastating in the future. To identify anti-viral measures interdisciplinary research is required at all levels, from basic virology to applied drug and vaccine development as well as societal studies. An important strategy is to identify novel anti-virals that target the host rather than the virus, akin to cancer therapy. This strategy is expected to reduce viral drug resistance, and provide complementary targets against the disease. SARS-CoV-2 replicates in the upper respiratory tract to high levels, and progresses to the lower respiratory tract where it causes inflammatory responses and exacerbates lung disease, particularly in people with preexisting lung conditions, or immune disfunctions. The high virulence of HCoV is due to viral interactions with the host during entry, replication and egress from the infected cells, and leads to the production of viral factors antagonizing the protective effects of host immunity components, such as interferon. Strategies blocking the viral effects on the host have to be identifed, and rapidly implemented for use in humans. Host targeting against viral infections has been a focus of the Greber lab at the University of Zurich. More recently, a collaboration of the Greber laboratory and the Turcatti laboratory at EPFL has screened a chemical library of about 1200 compounds in an image-based, full cycle test with human adenovirus. This screen uncovered a clinical compound, the HIV protease inhibitor Nelfinavir. Here, we propose a three-step procedure to identify novel chemical compounds against the pandemic strain SARS-CoV-2. Step one is a high-throughput drug screen against HCoV infection in human cell cultures, using a customized library of 5480 clinical and preclinical compounds, many of which are used in humans against non-viral disease. The initial screen will be conducted with an attenuated HCoV at biosafety level 2 (BSL2), measuring all the major virus replication steps, including entry, replication, assembly and spread to uninfected cells. Step two will test anti-HCoV compounds for efficacy against SARS-CoV-2 at BSL3 (collaboration with University of Bern). Step three will consider the most promising compounds for applicability in clinical trials against COVID-19, and in-depth follow up studies. Funding for clinical trials will be seeked by separate grant applications. In summary, our approach to identify novel clinically approved compounds against SARS-CoV-2 is unique in that it explores the complete viral replication cycle by an image-based automated procedure in human cell cultures. It presents an outstanding opportunity with translational potential. The project will provide an extensive amount of fully open-access data, which will spur follow-up projects exploring the cell biological mechanisms and mode-of-action of the newly repurposed anti-viral drugs against the highly disruptive COVID-19 disease.