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      Exploring the morphology of the host cell to open new possibilities for drug repurposing in viral infections

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            Abstract

            New approaches are needed to identify novel or repurposed drugs to treat deadly viral infections. Majority of screening methods evaluate the drug activity on a given virus while neglecting the host mechanisms and responses to the virus infection.Here, we investigate antiviral activity of 5200 compounds from the SPECS drug repurposing library by three distinct screening campaigns: 1) host cell morphology changes by phenomics assay Cell Painting 2) antibody-detection of SARS-CoV-2infection and 3) the gold-standard cytopathic effect method. We demonstrate how SARS-CoV-2 infection induced a specific phenotypic signature in Vero E6 cells, which was reversed by assay controls such as remdesivir. Our unbiased host-focused approach identified additional 324 compounds with antiviral activity against SARS-CoV-2.

            To further study the host response during infection, we quantified the subcellular localization and expression of 602 host proteins using antibodies from the Human Protein Atlas. We identified phenotypic responses to SARS-CoV-2 infection in 97 proteins. Finally, to broaden the paradigm of how antiviral therapies are identified we aim to combine these host-focused screening approaches. Our preliminary analyses have identified 3 host proteins linked to 3 compounds that reverse the virus-specific phenotype, which all represent novel drug repurposing candidates against SARS-CoV-2. Taken together, these findings illustrate a new host-centric approach for the discovery of antivirals and could be applied for other emerging or re-emerging viruses.

            Content

            Author and article information

            Conference
            RExPO23 Conference
            REPO4EU
            28 September 2023
            Affiliations
            [1 ] Department of Oncology and Pathology and Science for Life Laboratory, Karolinska Institutet, S-171 76, Stockholm, Sweden ( https://ror.org/056d84691)
            [2 ] Department of Pharmaceutical Biosciences and Science for Life Laboratory, Uppsala University, SE-75124, Uppsala, Sweden ( https://ror.org/048a87296)
            [3 ] Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet, S-17176, Stockholm, Sweden ( https://ror.org/056d84691)
            [4 ] Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, S-17176, Stockholm, Sweden ( https://ror.org/056d84691)
            [5 ] Division of Cellular and Clinical Proteomics, Science for Life Laboratory, Kungliga Tekniska Högskolan, SE-17121 Solna, Sweden ( https://ror.org/026vcq606)
            [6 ] Division of Cellular and Clinical Proteomics, Science for Life Laboratory, Kungliga Tekniska Högskolan, SE-17121 Solna, Sweden;
            [7 ] Chemical Biology Consortium Sweden (CBCS), Science for Life Laboratory, Karolinska Institutet, S-17176, Stockholm, Sweden;
            Author notes
            Author information
            https://orcid.org/0000-0001-5744-3206
            https://orcid.org/0000-0002-8083-2864
            Article
            10.58647/REXPO.23000018.v1
            fa810f18-9f56-461f-a0c1-a3cb0052b46b

            This work has been published open access under Creative Commons Attribution License CC BY 4.0 , which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Conditions, terms of use and publishing policy can be found at www.scienceopen.com .

            RExPO23
            2
            Stockholm, Sweden
            25-26 October 2023
            History
            : 28 September 2023
            Product

            REPO4EU

            Categories

            The datasets generated during and/or analysed during the current study are available from the corresponding author on reasonable request.
            Microbiology & Virology
            Drug repurposing,SARS-CoV-2,Antivirals,Cell Painting,Phenomics,Virology,High-content screening,Host-pathogen interactions

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