scholarly journals Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

2019 ◽  
Author(s):  
Jean A. Bernatchez ◽  
Michael Coste ◽  
Sungjun Beck ◽  
Grace A. Wells ◽  
Lucas A. Luna ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Nucleoside Analogue ◽  
Zika Virus ◽  
Active Metabolite ◽  
Cytopathic Effect ◽  
Cell Model ◽  
Strong Activity ◽  
Human Neural Stem Cells ◽  
Neurodevelopmental Impairment

AbstractZika virus (ZIKV), an emerging flavivirus which causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome, continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2′-C-methyluridine and 2′-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Conversion of the aryloxyl phosphoramidate ProTide group of 2′-C-methyluridine to a 2-(methylthio)ethyl phosphoramidate completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2′-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. Molecular superpositioning revealed different orientations of residues opposite the 2′-fluoro group of sofosbuvir. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.

scholarly journals Activity of Selected Nucleoside Analogue ProTides against Zika Virus in Human Neural Stem Cells

Viruses ◽  
2019 ◽  
Vol 11 (4) ◽  
pp. 365 ◽  
Author(s):  
Jean A. Bernatchez ◽  
Michael Coste ◽  
Sungjun Beck ◽  
Grace A. Wells ◽  
Lucas A. Luna ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Nucleoside Analogue ◽  
Zika Virus ◽  
Active Metabolite ◽  
Cytopathic Effect ◽  
Cell Model ◽  
Strong Activity ◽  
Human Neural Stem Cells ◽  
Neurodevelopmental Impairment

Zika virus (ZIKV), an emerging flavivirus that causes neurodevelopmental impairment to fetuses and has been linked to Guillain-Barré syndrome continues to threaten global health due to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) have been employed to improve the bioavailability of ribonucleoside analogues. Here, we synthesized and tested a small library of 13 ProTides against ZIKV in human neural stem cells. Strong activity was observed for 2′-C-methyluridine and 2′-C-ethynyluridine ProTides with an aryloxyl phosphoramidate masking group. Substitution of a 2-(methylthio) ethyl phosphoramidate for the aryloxyl phosphoramidate ProTide group of 2′-C-methyluridine completely abolished antiviral activity of the compound. The aryloxyl phosphoramidate ProTide of 2′-C-methyluridine outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and protection from cytopathic effect, while the former compound’s triphosphate active metabolite was better incorporated by purified ZIKV NS5 polymerase over time. These findings suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue ProTides in a disease-relevant cell model.

scholarly journals Zika virus impairs growth in human neurospheres and brain organoids

2016 ◽  
Author(s):  
Patricia P Garcez ◽  
Erick C Loiola ◽  
Rodrigo F Madeiro da Costa ◽  
Luiza Higa ◽  
Pablo Trindade ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Brain Development ◽  
Zika Virus ◽  
Brain Cells ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

scholarly journals Zika Virus Alters DNA Methylation of Neural Genes in an Organoid Model of the Developing Human Brain

mSystems ◽  
2018 ◽  
Vol 3 (1) ◽  
Author(s):  
Sylvie Janssens ◽  
Michael Schotsaert ◽  
Rahul Karnik ◽  
Vinod Balasubramaniam ◽  
Marion Dejosez ◽  
...  
Keyword(s):  
Dna Methylation ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Zika Virus ◽  
Brain Disorders ◽  
Epigenetic Changes ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Neural Genes

Scientific research on human neural stem cells and cerebral organoids has confirmed the congenital neurotropic and neurodestructive nature of the Zika virus. However, the extent to which prenatal ZIKV infection is associated with more subtle brain alterations, such as epigenetic changes, remains ill defined. Here, we address the question of whether ZIKV infection induces DNA methylation changes with the potential to cause brain disorders later in life.

scholarly journals Zika Virus Impairs Neurogenesis and Synaptogenesis Pathways in Human Neural Stem Cells and Neurons

2019 ◽  
Vol 13 ◽  
Author(s):  
Livia Rosa-Fernandes ◽  
Fernanda Rodrigues Cugola ◽  
Fabiele Baldino Russo ◽  
Rebeca Kawahara ◽  
Caio Cesar de Melo Freire ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Zika Virus ◽  
Human Neural Stem Cells

scholarly journals Zika virus impairs growth in human neurospheres and brain organoids

2016 ◽  
Author(s):  
Patricia P Garcez ◽  
Erick C Loiola ◽  
Rodrigo F Madeiro da Costa ◽  
Luiza Higa ◽  
Pablo Trindade ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Brain Development ◽  
Zika Virus ◽  
Brain Cells ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

scholarly journals Zika virus impairs growth in human neurospheres and brain organoids

2016 ◽  
Author(s):  
Patricia P Garcez ◽  
Erick C Loiola ◽  
Rodrigo F Madeiro da Costa ◽  
Luiza Higa ◽  
Pablo Trindade ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Brain Development ◽  
Zika Virus ◽  
Brain Cells ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

scholarly journals Bioinformatic analysis reveals the expression of unique transcriptomic signatures in Zika virus infected human neural stem cells

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Alyssa J. Rolfe ◽  
Dale B. Bosco ◽  
Jingying Wang ◽  
Richard S. Nowakowski ◽  
Jianqing Fan ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Zika Virus ◽  
Bioinformatic Analysis ◽  
Human Neural Stem Cells

scholarly journals Zika virus impairs growth in human neurospheres and brain organoids

2016 ◽  
Author(s):  
Patricia P Garcez ◽  
Erick C Loiola ◽  
Rodrigo F Madeiro da Costa ◽  
Luiza Higa ◽  
Pablo Trindade ◽  
...  
Keyword(s):  
Electron Microscopy ◽  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Brain ◽  
Brain Development ◽  
Zika Virus ◽  
Brain Cells ◽  
Zikv Infection ◽  
Human Neural Stem Cells ◽  
Human Brain Development

Since the emergence of Zika virus (ZIKV), reports of microcephaly have increased dramatically in Brazil; however, causality between the widespread epidemic and malformations in fetal brains has not been confirmed. Here, we examine the effects of ZIKV infection in human neural stem cells growing as neurospheres and cerebral organoids. Using immunocytochemistry and electron microscopy, we show that ZIKV targets human brain cells, reducing their viability and growth as neurospheres and cerebral organoids. These results suggest that ZIKV abrogates neurogenesis during human brain development.

scholarly journals mRNA-Driven Generation of Transgene-Free Neural Stem Cells from Human Urine-Derived Cells

Cells ◽  
2019 ◽  
Vol 8 (9) ◽  
pp. 1043 ◽  
Author(s):  
Phil Jun Kang ◽  
Daryeon Son ◽  
Tae Hee Ko ◽  
Wonjun Hong ◽  
Wonjin Yun ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Human Urine ◽  
Neurological Disorders ◽  
Therapeutic Potential ◽  
Embryonic Stem ◽  
Global Gene Expression ◽  
Patient Specific ◽  
Human Neural Stem Cells

Human neural stem cells (NSCs) hold enormous promise for neurological disorders, typically requiring their expandable and differentiable properties for regeneration of damaged neural tissues. Despite the therapeutic potential of induced NSCs (iNSCs), a major challenge for clinical feasibility is the presence of integrated transgenes in the host genome, contributing to the risk for undesired genotoxicity and tumorigenesis. Here, we describe the advanced transgene-free generation of iNSCs from human urine-derived cells (HUCs) by combining a cocktail of defined small molecules with self-replicable mRNA delivery. The established iNSCs were completely transgene-free in their cytosol and genome and further resembled human embryonic stem cell-derived NSCs in the morphology, biological characteristics, global gene expression, and potential to differentiate into functional neurons, astrocytes, and oligodendrocytes. Moreover, iNSC colonies were observed within eight days under optimized conditions, and no teratomas formed in vivo, implying the absence of pluripotent cells. This study proposes an approach to generate transplantable iNSCs that can be broadly applied for neurological disorders in a safe, efficient, and patient-specific manner.

scholarly journals BCOR Internal Tandem Duplication Expression in Neural Stem Cells Promotes Growth, Invasion, and Expression of PRC2 Targets

2021 ◽  
Vol 22 (8) ◽  
pp. 3913
Author(s):  
Satoshi Nakata ◽  
Ming Yuan ◽  
Jeffrey A. Rubens ◽  
Ulf D. Kahlert ◽  
Jarek Maciaczyk ◽  
...  
Keyword(s):  
Stem Cells ◽  
Neural Stem Cells ◽  
Tandem Duplication ◽  
Target Genes ◽  
Cellular Growth ◽  
Central Nervous System Tumor ◽  
Internal Tandem Duplication ◽  
Invasion And Migration ◽  
Human Neural Stem Cells ◽  
And Migration

Central nervous system tumor with BCL6-corepressor internal tandem duplication (CNS-BCOR ITD) is a malignant entity characterized by recurrent alterations in exon 15 encoding the essential binding domain for the polycomb repressive complex (PRC). In contrast to deletion or truncating mutations seen in other tumors, BCOR expression is upregulated in CNS-BCOR ITD, and a distinct oncogenic mechanism has been suggested. However, the effects of this change on the biology of neuroepithelial cells is poorly understood. In this study, we introduced either wildtype BCOR or BCOR-ITD into human and murine neural stem cells and analyzed them with quantitative RT-PCR and RNA-sequencing, as well as growth, clonogenicity, and invasion assays. In human cells, BCOR-ITD promoted derepression of PRC2-target genes compared to wildtype BCOR. A similar effect was found in clinical specimens from previous studies. However, no growth advantage was seen in the human neural stem cells expressing BCOR-ITD, and long-term models could not be established. In the murine cells, both wildtype BCOR and BCOR-ITD overexpression affected cellular differentiation and histone methylation, but only BCOR-ITD increased cellular growth, invasion, and migration. BCOR-ITD overexpression drives transcriptional changes, possibly due to altered PRC function, and contributes to the oncogenic transformation of neural precursors.

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