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  1. Article ; Online: Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids.

    Pettke, Aleksandra / Tampere, Marianna / Pronk, Robin / Wallner, Olov / Falk, Anna / Warpman Berglund, Ulrika / Helleday, Thomas / Mirazimi, Ali / Puumalainen, Marjo-Riitta

    Viruses

    2020  Volume 13, Issue 1

    Abstract: RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects ... ...

    Abstract RNA viruses have gained plenty of attention during recent outbreaks of Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), Zika virus (ZIKV), and Ebola virus. ZIKV is a vector borne Flavivirus that is spread by mosquitoes and it mainly infects neuronal progenitor cells. One hallmark of congenital ZIKV disease is a reduced brain size in fetuses, leading to severe neurological defects. The World Health Organization (WHO) is urging the development of new antiviral treatments against ZIKV, as there are no efficient countermeasures against ZIKV disease. Previously, we presented a new class of host-targeting antivirals active against a number of pathogenic RNA viruses, such as SARS-CoV-2. Here, we show the transfer of the image-based phenotypic antiviral assay to ZIKV-infected brain cells, followed by mechanism-of-action studies and a proof-of-concept study in a three-dimensional (3D) organoid model. The novel antiviral compounds showed a therapeutic window against ZIKV in several cell models and rescued ZIKV-induced neurotoxicity in brain organoids. The compound's mechanism-of-action was pinpointed to late steps in the virus life cycle, impairing the formation of new virus particles. Collectively, in this study, we expand the antiviral activity of new small molecule inhibitors to a new virus class of Flaviviruses, but also uncover compounds' mechanism of action, which are important for the further development of antivirals.
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; Brain/metabolism ; Brain/pathology ; COVID-19 ; Cell Survival/drug effects ; Humans ; Organoids/metabolism ; Organoids/pathology ; RNA Viruses ; Ribavirin/pharmacology ; SARS-CoV-2 ; Zika Virus/drug effects ; Zika Virus/physiology ; Zika Virus Infection/metabolism ; Zika Virus Infection/virology
    Chemical Substances Antiviral Agents ; Ribavirin (49717AWG6K)
    Language English
    Publishing date 2020-12-29
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v13010037
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  2. Article ; Online: A phenomics approach for antiviral drug discovery.

    Rietdijk, Jonne / Tampere, Marianna / Pettke, Aleksandra / Georgiev, Polina / Lapins, Maris / Warpman-Berglund, Ulrika / Spjuth, Ola / Puumalainen, Marjo-Riitta / Carreras-Puigvert, Jordi

    BMC biology

    2021  Volume 19, Issue 1, Page(s) 156

    Abstract: Background: The emergence and continued global spread of the current COVID-19 pandemic has highlighted the need for methods to identify novel or repurposed therapeutic drugs in a fast and effective way. Despite the availability of methods for the ... ...

    Abstract Background: The emergence and continued global spread of the current COVID-19 pandemic has highlighted the need for methods to identify novel or repurposed therapeutic drugs in a fast and effective way. Despite the availability of methods for the discovery of antiviral drugs, the majority tend to focus on the effects of such drugs on a given virus, its constituent proteins, or enzymatic activity, often neglecting the consequences on host cells. This may lead to partial assessment of the efficacy of the tested anti-viral compounds, as potential toxicity impacting the overall physiology of host cells may mask the effects of both viral infection and drug candidates. Here we present a method able to assess the general health of host cells based on morphological profiling, for untargeted phenotypic drug screening against viral infections.
    Results: We combine Cell Painting with antibody-based detection of viral infection in a single assay. We designed an image analysis pipeline for segmentation and classification of virus-infected and non-infected cells, followed by extraction of morphological properties. We show that this methodology can successfully capture virus-induced phenotypic signatures of MRC-5 human lung fibroblasts infected with human coronavirus 229E (CoV-229E). Moreover, we demonstrate that our method can be used in phenotypic drug screening using a panel of nine host- and virus-targeting antivirals. Treatment with effective antiviral compounds reversed the morphological profile of the host cells towards a non-infected state.
    Conclusions: The phenomics approach presented here, which makes use of a modified Cell Painting protocol by incorporating an anti-virus antibody stain, can be used for the unbiased morphological profiling of virus infection on host cells. The method can identify antiviral reference compounds, as well as novel antivirals, demonstrating its suitability to be implemented as a strategy for antiviral drug repurposing and drug discovery.
    MeSH term(s) Antiviral Agents/pharmacology ; Cell Line ; Dose-Response Relationship, Drug ; Drug Discovery/methods ; Drug Evaluation, Preclinical/methods ; Humans ; Phenomics/methods ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology
    Chemical Substances Antiviral Agents
    Language English
    Publishing date 2021-08-02
    Publishing country England
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2133020-7
    ISSN 1741-7007 ; 1741-7007
    ISSN (online) 1741-7007
    ISSN 1741-7007
    DOI 10.1186/s12915-021-01086-1
    Database MEDical Literature Analysis and Retrieval System OnLINE

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  3. Article ; Online: A phenomics approach for antiviral drug discovery

    Jonne Rietdijk / Marianna Tampere / Aleksandra Pettke / Polina Georgiev / Maris Lapins / Ulrika Warpman-Berglund / Ola Spjuth / Marjo-Riitta Puumalainen / Jordi Carreras-Puigvert

    BMC Biology, Vol 19, Iss 1, Pp 1-

    2021  Volume 15

    Abstract: Abstract Background The emergence and continued global spread of the current COVID-19 pandemic has highlighted the need for methods to identify novel or repurposed therapeutic drugs in a fast and effective way. Despite the availability of methods for the ...

    Abstract Abstract Background The emergence and continued global spread of the current COVID-19 pandemic has highlighted the need for methods to identify novel or repurposed therapeutic drugs in a fast and effective way. Despite the availability of methods for the discovery of antiviral drugs, the majority tend to focus on the effects of such drugs on a given virus, its constituent proteins, or enzymatic activity, often neglecting the consequences on host cells. This may lead to partial assessment of the efficacy of the tested anti-viral compounds, as potential toxicity impacting the overall physiology of host cells may mask the effects of both viral infection and drug candidates. Here we present a method able to assess the general health of host cells based on morphological profiling, for untargeted phenotypic drug screening against viral infections. Results We combine Cell Painting with antibody-based detection of viral infection in a single assay. We designed an image analysis pipeline for segmentation and classification of virus-infected and non-infected cells, followed by extraction of morphological properties. We show that this methodology can successfully capture virus-induced phenotypic signatures of MRC-5 human lung fibroblasts infected with human coronavirus 229E (CoV-229E). Moreover, we demonstrate that our method can be used in phenotypic drug screening using a panel of nine host- and virus-targeting antivirals. Treatment with effective antiviral compounds reversed the morphological profile of the host cells towards a non-infected state. Conclusions The phenomics approach presented here, which makes use of a modified Cell Painting protocol by incorporating an anti-virus antibody stain, can be used for the unbiased morphological profiling of virus infection on host cells. The method can identify antiviral reference compounds, as well as novel antivirals, demonstrating its suitability to be implemented as a strategy for antiviral drug repurposing and drug discovery.
    Keywords Phenomics ; Morphological profiling ; Cell Painting ; Drug discovery ; Antiviral ; Biology (General) ; QH301-705.5
    Subject code 570
    Language English
    Publishing date 2021-08-01T00:00:00Z
    Publisher BMC
    Document type Article ; Online
    Database BASE - Bielefeld Academic Search Engine (life sciences selection)

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  4. Article ; Online: Subcellular mapping of the protein landscape of SARS-CoV-2 infected cells for target-centric drug repurposing

    Kaimal, Jayasankar Mohanakrishnan / Tampere, Marianna / Le, Trang H / Axelsson, Ulrika / Xu, Hao / Axelsson, Hanna / Backstrom, Anna / Marabita, Francesco / Moussaud-Lamodiere, Elisabeth / Njenda, Duncan / Sepulveda, Carolina Oses / Ouyang, Wei / Seashore-Ludlow, Brinton / Vernersson, Caroline / Mirazimi, Ali / Lundberg, Emma / Ostling, Paivi / Stadler, Charlotte

    bioRxiv

    Abstract: The COVID-19 pandemic has resulted in millions of deaths and affected socioeconomic structure worldwide and the search for new antivirals and treatments are still ongoing. In the search for new drug target and to increase our understanding of the disease, ...

    Abstract The COVID-19 pandemic has resulted in millions of deaths and affected socioeconomic structure worldwide and the search for new antivirals and treatments are still ongoing. In the search for new drug target and to increase our understanding of the disease, we used large scale immunofluorescence to explore the host cell response to SARS-CoV-2 infection. Among the 602 host proteins studied in this host response screen, changes in abundance and subcellular localization were observed for 97 proteins, with 45 proteins showing increased abundance and 10 reduced abundances. 20 proteins displayed changed localization upon infection and an additional 22 proteins displayed altered abundance and localization, together contributing to diverse reshuffling of the host cell protein landscape. We then selected existing and approved small-molecule drugs (n =123) against our identified host response proteins and identified 3 compounds - elesclomol, crizotinib and rimcazole, that significantly reduced antiviral activity. Our study introduces a novel, targeted and systematic approach based on host protein profiling, to identify new targets for drug repurposing. The dataset of ~75,000 immunofluorescence images from this study are published as a resource available for further studies.
    Keywords covid19
    Language English
    Publishing date 2022-03-29
    Publisher Cold Spring Harbor Laboratory
    Document type Article ; Online
    DOI 10.1101/2022.03.29.482838
    Database COVID19

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  5. Article ; Online: Novel Broad-Spectrum Antiviral Inhibitors Targeting Host Factors Essential for Replication of Pathogenic RNA Viruses.

    Tampere, Marianna / Pettke, Aleksandra / Salata, Cristiano / Wallner, Olov / Koolmeister, Tobias / Cazares-Körner, Armando / Visnes, Torkild / Hesselman, Maria Carmen / Kunold, Elena / Wiita, Elisee / Kalderén, Christina / Lightowler, Molly / Jemth, Ann-Sofie / Lehtiö, Janne / Rosenquist, Åsa / Warpman-Berglund, Ulrika / Helleday, Thomas / Mirazimi, Ali / Jafari, Rozbeh /
    Puumalainen, Marjo-Riitta

    Viruses

    2020  Volume 12, Issue 12

    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 ... ...

    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.
    MeSH term(s) Animals ; Antiviral Agents/pharmacology ; Cell Line ; Ebolavirus/drug effects ; Ebolavirus/physiology ; HSP70 Heat-Shock Proteins/metabolism ; Hemorrhagic Fever Virus, Crimean-Congo/drug effects ; Hemorrhagic Fever Virus, Crimean-Congo/physiology ; Host-Pathogen Interactions/drug effects ; Humans ; Protein Binding/drug effects ; Protein Stability ; Proteome/drug effects ; Proteostasis/drug effects ; RNA Virus Infections/metabolism ; RNA Virus Infections/virology ; RNA Viruses/drug effects ; RNA Viruses/physiology ; SARS-CoV-2/drug effects ; SARS-CoV-2/physiology ; Small Molecule Libraries/pharmacology ; Viral Proteins/metabolism ; Virus Replication/drug effects
    Chemical Substances Antiviral Agents ; HSP70 Heat-Shock Proteins ; Proteome ; Small Molecule Libraries ; Viral Proteins
    Language English
    Publishing date 2020-12-10
    Publishing country Switzerland
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ZDB-ID 2516098-9
    ISSN 1999-4915 ; 1999-4915
    ISSN (online) 1999-4915
    ISSN 1999-4915
    DOI 10.3390/v12121423
    Database MEDical Literature Analysis and Retrieval System OnLINE

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