Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids
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 con...
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doaj-c9fd92c6119b4b968966074b04ef93932020-12-30T00:03:48ZengMDPI AGViruses1999-49152021-12-0113373710.3390/v13010037Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain OrganoidsAleksandra Pettke0Marianna Tampere1Robin Pronk2Olov Wallner3Anna Falk4Ulrika Warpman Berglund5Thomas Helleday6Ali Mirazimi7Marjo-Riitta Puumalainen8Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, SwedenScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, 171 77 Stockholm, SwedenScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, SwedenDepartment of Neuroscience, Karolinska Institutet, 171 77 Stockholm, SwedenScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, SwedenScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, SwedenNational Veterinary Institute, 756 51 Uppsala, SwedenScience for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, SwedenRNA 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.https://www.mdpi.com/1999-4915/13/1/37Zika viruspathogenic RNA virusesantiviralsbrain organoidsmode-of-action |
collection |
DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Aleksandra Pettke Marianna Tampere Robin Pronk Olov Wallner Anna Falk Ulrika Warpman Berglund Thomas Helleday Ali Mirazimi Marjo-Riitta Puumalainen |
spellingShingle |
Aleksandra Pettke Marianna Tampere Robin Pronk Olov Wallner Anna Falk Ulrika Warpman Berglund Thomas Helleday Ali Mirazimi Marjo-Riitta Puumalainen Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids Viruses Zika virus pathogenic RNA viruses antivirals brain organoids mode-of-action |
author_facet |
Aleksandra Pettke Marianna Tampere Robin Pronk Olov Wallner Anna Falk Ulrika Warpman Berglund Thomas Helleday Ali Mirazimi Marjo-Riitta Puumalainen |
author_sort |
Aleksandra Pettke |
title |
Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids |
title_short |
Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids |
title_full |
Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids |
title_fullStr |
Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids |
title_full_unstemmed |
Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids |
title_sort |
broadly active antiviral compounds disturb zika virus progeny release rescuing virus-induced toxicity in brain organoids |
publisher |
MDPI AG |
series |
Viruses |
issn |
1999-4915 |
publishDate |
2021-12-01 |
description |
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. |
topic |
Zika virus pathogenic RNA viruses antivirals brain organoids mode-of-action |
url |
https://www.mdpi.com/1999-4915/13/1/37 |
work_keys_str_mv |
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