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Volume 13
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10.3390/v13010037
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Article

Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids

by
Aleksandra Pettke
1,†,
Marianna Tampere
1,2,†,
Robin Pronk
3,
Olov Wallner
1,
Anna Falk
3,
Ulrika Warpman Berglund
1,
Thomas Helleday
1,
Ali Mirazimi
2,4 and
Marjo-Riitta Puumalainen
1,*
1
Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, Sweden
2
National Veterinary Institute, 756 51 Uppsala, Sweden
3
Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden
4
Unit of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institute and Karolinska University Hospital, 171 77 Stockholm, Sweden
*
Author to whom correspondence should be addressed.
†
Authors contributed equally.
Viruses 2021, 13(1), 37; https://doi.org/10.3390/v13010037
Submission received: 26 November 2020 / Revised: 22 December 2020 / Accepted: 24 December 2020 / Published: 29 December 2020
(This article belongs to the Special Issue Cell, Organoid and Animal Models to Study Pathogenic Human RNA Viruses)
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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.
Keywords: Zika virus; pathogenic RNA viruses; antivirals; brain organoids; mode-of-action Zika virus; pathogenic RNA viruses; antivirals; brain organoids; mode-of-action

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MDPI and ACS Style

Pettke, A.; Tampere, M.; Pronk, R.; Wallner, O.; Falk, A.; Warpman Berglund, U.; Helleday, T.; Mirazimi, A.; Puumalainen, M.-R. Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids. Viruses 2021, 13, 37. https://doi.org/10.3390/v13010037

AMA Style

Pettke A, Tampere M, Pronk R, Wallner O, Falk A, Warpman Berglund U, Helleday T, Mirazimi A, Puumalainen M-R. Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids. Viruses. 2021; 13(1):37. https://doi.org/10.3390/v13010037

Chicago/Turabian Style

Pettke, Aleksandra, Marianna Tampere, Robin Pronk, Olov Wallner, Anna Falk, Ulrika Warpman Berglund, Thomas Helleday, Ali Mirazimi, and Marjo-Riitta Puumalainen. 2021. "Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids" Viruses 13, no. 1: 37. https://doi.org/10.3390/v13010037

APA Style

Pettke, A., Tampere, M., Pronk, R., Wallner, O., Falk, A., Warpman Berglund, U., Helleday, T., Mirazimi, A., & Puumalainen, M.-R. (2021). Broadly Active Antiviral Compounds Disturb Zika Virus Progeny Release Rescuing Virus-Induced Toxicity in Brain Organoids. Viruses, 13(1), 37. https://doi.org/10.3390/v13010037

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