Abstract
Recent RNA virus outbreaks such as Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and Ebola virus (EBOV) have caused worldwide health emergencies highlighting the urgent need for new antiviral strategies. Targeting host cell pathways supporting viral replication is an attractive approach for development of antiviral compounds, especially with new, unexplored viruses where knowledge of virus biology is limited. Here, we present a strategy to identify host-targeted small molecule inhibitors using an image-based phenotypic antiviral screening assay followed by extensive target identification efforts revealing altered cellular pathways upon antiviral compound treatment. The newly discovered antiviral compounds showed broad-range antiviral activity against pathogenic RNA viruses such as SARS-CoV-2, EBOV and Crimean-Congo hemorrhagic fever virus (CCHFV). Target identification of the antiviral compounds by thermal protein profiling revealed major effects on proteostasis pathways and disturbance in interactions between cellular HSP70 complex and viral proteins, illustrating the supportive role of HSP70 on many RNA viruses across virus families. Collectively, this strategy identifies new small molecule inhibitors with broad antiviral activity against pathogenic RNA viruses, but also uncovers novel virus biology urgently needed for design of new antiviral therapies.
Highlights
In the last decade, we have seen outbreaks of several pathogenic RNA viruses, like Ebola virus (EBOV), Crimean-Congo hemorrhagic fever virus (CCHFV) and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2)
Since screening for antivirals in high-containment biosafety level (BSL) settings is challenging, human non-pathogenic Hazara virus (HAZV), that belongs to the same serogroup of CCHFV [35] but can be handled in a BSL2 laboratory, was chosen
To assess antiviral activity and cytotoxicity of tested compounds, percentage of HAZV-infected cells and nuclei count were quantified by high-throughput microscopy and automated image analysis using CellProfiler software (Broad Institute, Cambridge, MA, USA) (Figure 1A)
Summary
We have seen outbreaks of several pathogenic RNA viruses, like Ebola virus (EBOV), Crimean-Congo hemorrhagic fever virus (CCHFV) and Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2). EBOV and CCHFV both cause viral hemorrhagic fever with the average case fatality rate around 50–70% [1,2,3] and 5–30% [4], respectively. The ongoing Coronavirus disease 2019 (COVID-19) pandemic caused by SARS-CoV-2 has led to 1,200,000 deaths as of November 2020 and unseen social and economic disruption worldwide. Common human coronaviruses such as Coronavirus 229E (CoV 229E) cause mild upper respiratory tract infections and around 15–30% of common cold cases in adults [5]. While RNA viruses cause a variety of diseases, a common denominator is the lack of antivirals to treat them, highlighting the need for the development of antivirals to tackle these diseases
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