Abstract
Viruses are a major threat to human health and economic well-being. In recent years Ebola, Zika, influenza, and chikungunya virus epidemics have raised awareness that infections can spread rapidly before vaccines or specific antagonists can be made available. Broad-spectrum antivirals are drugs with the potential to inhibit infection by viruses from different groups or families, which may be deployed during outbreaks when specific diagnostics, vaccines or directly acting antivirals are not available. While pathogen-directed approaches are generally effective against a few closely related viruses, targeting cellular pathways used by multiple viral agents can have broad-spectrum efficacy. Virus entry, particularly clathrin-mediated endocytosis, constitutes an attractive target as it is used by many viruses. Using a phenotypic screening strategy where the inhibitory activity of small molecules was sequentially tested against different viruses, we identified 12 compounds with broad-spectrum activity, and found a subset blocking viral internalisation and/or fusion. Importantly, we show that compounds identified with this approach can reduce viral replication in a mouse model of Zika infection. This work provides proof of concept that it is possible to identify broad-spectrum inhibitors by iterative phenotypic screenings, and that inhibition of host-pathways critical for viral life cycles can be an effective antiviral strategy.
Highlights
IntroductionIn recent years epidemics of Ebola [1], Zika [2], yellow fever [3], influenza [4], and chikungunya [5] viruses amongst others have raised awareness that viruses can spread rapidly and extensively before vaccines can be developed or made available to affected populations
Emerging and re-emerging viruses present a major threat to human and animal health
When we examined which blood cell populations where infected with Zika Virus (ZIKV) and whether any compound reduced the number of infected cells in the blood by immunostaining, we observed very limited/no infection of CD8+ T cells (Figure S3C) and detectable infection of CD14+CD11b+
Summary
In recent years epidemics of Ebola [1], Zika [2], yellow fever [3], influenza [4], and chikungunya [5] viruses amongst others have raised awareness that viruses can spread rapidly and extensively before vaccines can be developed or made available to affected populations. The development of virus-specific vaccines or directly-acting antivirals (DAA) can be a lengthy process, fraught with difficulties and challenges. In the face of a new viral outbreak, it is rare for a new vaccine or DAA to be made available for clinical use in time to make a difference. BSA are attractive because they can be deployed rapidly during epidemics of emerging or re-emerging viruses without the need for accurate diagnostics, or when specific vaccines or therapies are not available. By targeting cellular rather than viral components, the risk of selecting for viral resistance is much lower [8]
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