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

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.

Human Brain Organoids as an In Vitro Model System of Viral Infectious Diseases

“…The broadly active antiviral compound TH6744 interferes with the ZIKV life cycle of RNA replication, with the synthesis, posttreatment, or stability of viral proteins, and with the assembly, transport, or budding of viral particles in the brain organoid model. Therefore, TH6744 can not only alleviate the pathogenic phenotype induced by ZIKV, but also blocks the transmission of the virus ( 33 ).…”

The Age of Brain Organoids: Tailoring Cell Identity and Functionality for Normal Brain Development and Disease Modeling

“…Infection of human brain organoids has been used for the screening of compounds and drug repurposing to treat infection (Xu et al, 2016(Xu et al, , 2019Watanabe et al, 2017;Pettke et al, 2020). Strikingly, brain organoids were used by our group to establish a connection between ZIKV infection and the regional increase in the cases of microcephaly in the northeast of Brazil.…”

Methodologies for Generating Brain Organoids to Model Viral Pathogenesis in the CNS

“…Virus researchers typically present data from brain organoids derived from a single cell line, although some recent studies have derived brain organoids from two unique cell lines [55,[61][62][63][64][65][66]. While dozens of organoids can be produced through a single generation protocol, the resultant organoids are basically clones of each other and donor-specific characteristics persist in unique cell lines.…”