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A platform of assays for the discovery of anti-Zika small-molecules with activity in a 3D-bioprinted outer-blood-retina model
- Source :
- PLoS ONE, Vol 17, Iss 1, p e0261821 (2022), PLoS ONE
- Publication Year :
- 2022
- Publisher :
- Public Library of Science (PLoS), 2022.
-
Abstract
- The global health emergency posed by the outbreak of Zika virus (ZIKV), an arthropod-borne flavivirus causing severe neonatal neurological conditions, has subsided, but there continues to be transmission of ZIKV in endemic regions. As such, there is still a medical need for discovering and developing therapeutical interventions against ZIKV. To identify small-molecule compounds that inhibit ZIKV disease and transmission, we screened multiple small-molecule collections, mostly derived from natural products, for their ability to inhibit wild-type ZIKV. As a primary high-throughput screen, we used a viral cytopathic effect (CPE) inhibition assay conducted in Vero cells that was optimized and miniaturized to a 1536-well format. Suitably active compounds identified from the primary screen were tested in a panel of orthogonal assays using recombinant Zika viruses, including a ZIKV Renilla luciferase reporter assay and a ZIKV mCherry reporter system. Compounds that were active in the wild-type ZIKV inhibition and ZIKV reporter assays were further evaluated for their inhibitory effects against other flaviviruses. Lastly, we demonstrated that wild-type ZIKV is able to infect a 3D-bioprinted outer-blood-retina barrier tissue model and disrupt its barrier function, as measured by electrical resistance. One of the identified compounds (3-Acetyl-13-deoxyphomenone, NCGC00380955) was able to prevent the pathological effects of the viral infection on this clinically relevant ZIKV infection model.
- Subjects :
- RNA viruses
Cell Lines
Science
Drug Evaluation, Preclinical
Library Screening
Pathology and Laboratory Medicine
Research and Analysis Methods
Toxicology
Virus Replication
Microbiology
Antiviral Agents
Models, Biological
Retina
Virology
Chlorocebus aethiops
Medicine and Health Sciences
Animals
Humans
Molecular Biology Techniques
Microbial Pathogens
Vero Cells
Molecular Biology
Enzyme Assays
Molecular Biology Assays and Analysis Techniques
Multidisciplinary
Cytotoxicity Assay
Biology and life sciences
Flaviviruses
Zika Virus Infection
Luciferase Assay
Organisms
Zika Virus
Hep G2 Cells
Dengue Virus
Viral Replication
Bioassays and Physiological Analysis
Medical Microbiology
Viral Pathogens
Viruses
Printing, Three-Dimensional
Medicine
Biological Cultures
Pathogens
Biochemical Analysis
Research Article
Subjects
Details
- Language :
- English
- ISSN :
- 19326203
- Volume :
- 17
- Issue :
- 1
- Database :
- OpenAIRE
- Journal :
- PLoS ONE
- Accession number :
- edsair.doi.dedup.....12da6f37d435aeafa4ecda8cb40508a3