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

Viruses

Anna Falk¹  Robin Pronk¹  Ali Mirazimi²  Marianna Tampere³  Aleksandra Pettke³  Ulrika Warpman Berglund³  Thomas Helleday³  Olov Wallner³  Marjo-Riitta Puumalainen³ 

[1] Department of Neuroscience, Karolinska Institutet, 171 77 Stockholm, Sweden;National Veterinary Institute, 756 51 Uppsala, Sweden;Science for Life Laboratory, Department of Oncology-Pathology, Karolinska Institutet, 171 65 Stockholm, Sweden;

关键词: Zika virus;    pathogenic RNA viruses;    antivirals;    brain organoids;    mode-of-action;   

DOI  :  10.3390/v13010037

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown