Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate

Chen, Qi; Wu, Jin; Ye, Qing; Ma, Feng; Zhu, Qing; Wu, Yan; Shan, Chao; Xie, Xuping; Li, Dapei; Zhan, Xiaoyan; Li, Chunfeng; Li, Xiao Feng; Qin, Xiaoxia; Zhao, Tongyang; Wu, Haitao; Shi, Pei Yong; Man, Jianghong; Cheng, Qi

doi:10.1128/mbio.01683-18

Cited by 87 publications

(109 citation statements)

References 38 publications

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“…We and others have previously shown that certain lines of brain tumors with stem cell-like genetic programs, such as glioblastomas, are highly susceptible to ZIKV infection [29,45–47]. These cells display a striking phenotypic change upon infection.…”

Section: Resultsmentioning

confidence: 99%

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

Bernatchez

Coste

Beck

et al. 2019

Preprint

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Zika virus (ZIKV), an emerging flavivirus which causes neurodevelopmental impairment 22 to fetuses and has been linked to Guillain-Barré syndrome, continues to threaten global health due 23 to the absence of targeted prophylaxis or treatment. Nucleoside analogues are good examples of 24 efficient anti-viral inhibitors, and prodrug strategies using phosphate masking groups (ProTides) 25 have been employed to improve the bioavailability of ribonucleoside analogues. Here, we 26 synthesized and tested a library of 13 ProTides against ZIKV in human neural stem cells. Strong 27 activity was observed for 2'-C-methyluridine and 2'-C-ethynyluridine ProTides with an aryloxyl 28 phosphoramidate masking group. Conversion of the aryloxyl phosphoramidate ProTide group of 29 2'-C-methyluridine to a 2-(methylthio)ethyl phosphoramidate completely abolished antiviral 30 activity of the compound. The aryloxyl phosphoramidate ProTide of 2'-C-methyluridine 31 outperformed the hepatitis C virus (HCV) drug sofosbuvir in suppression of viral titers and 32 protection from cytopathic effect, while the former compound's triphosphate active metabolite was 33 better incorporated by purified ZIKV NS5 polymerase over time. Molecular superpositioning 34 revealed different orientations of residues opposite the 2'-fluoro group of sofosbuvir. These findings 35 suggest both a nucleobase and ProTide group bias for the anti-ZIKV activity of nucleoside analogue 36 ProTides in a disease-relevant cell model. 37 38 cells, RNA-dependent RNA polymerase 39 40 1. Introduction 41The explosive spread of Zika virus (ZIKV) during the 2015-2016 epidemics in Latin America 42 attracted worldwide attention to this previously neglected disease. The lack of effective vaccines or 43 small molecules to prevent or treat this infection remains a cause for concern and emphasizes the 44 urgent need for new therapeutic options [1]. ZIKV, an emerging flavivirus infection, causes several 48 manifestations of the disease, and in rare cases, ZIKV infection has been linked to the 49 neuroinflammatory Guillain-Barré syndrome [2]. 50 Viral polymerases remain attractive drug targets for the development of selective antiviral 51 therapies [3-5]. Generally, clinically-approved inhibitors that target these proteins fall into two broad 52 classes [6,7]. The first class consists of nucleoside analogues that mimic the natural substrate of the 53 enzyme. Upon analogue incorporation by the virally-encoded polymerase, DNA or RNA synthesis 54 is abrogated by preventing further nucleotide incorporation (chain termination), thereby arresting 55 viral replication. The second class is known as non-nucleoside inhibitors, which bind allosterically 56 and arrest viral nucleic acid synthesis by distorting the polymerase active site geometry to interfere 57 with nucleotide binding or nucleotide incorporation. 58 A common prodrug strategy used for antiviral ribonucleoside analogues involves the chemical 59 synthesis of nucleoside analogue monophosphates with metabolically-removable masking groups 60 [8...

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Section: Resultsmentioning

confidence: 99%

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

Bernatchez

Coste

Beck

et al. 2019

Preprint

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“…Specifically, glycine mutations affecting exon 49 of the COL1A2 gene was associated with an increased risk of intracranial bleeding 34 . Both collagen and LOX genes are stimulated in glioblastoma cells, and the suppression of this pathway by ZIKV infection could explain the decreasing of angiogenesis and anticancer effects that several authors are exploring to treat glioblastoma [35][36][37] with ZIKV-like particles.…”

Section: Discussionmentioning

confidence: 99%

The potential role of collagens in congenital Zika syndrome: A systems biology approach

Aguiar

Pohl

Morais³

et al. 2019

Preprint

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Zika virus (ZIKV) infection during pregnancy could cause a set of severe abnormalities in the fetus known as congenital Zika syndrome (CZS).Experiments using animal models and in vitro systems significantly contributed to our understanding of the physiopathology of ZIKV infection. However, the molecular basis of CZS is not yet studied in humans. Here, we used a systems biology approach to integrate transcriptomic, proteomic and genomic data from post-mortem brains of neonates with CZS. We observed that collagen genes were greatly reduced in CZS brains at both the RNA and protein levels and that neonates with CZS have several polymorphisms in collagen genes associated with osteogenesis imperfect and arthrogryposis. These findings were validated using immunohistochemistry and collagen staining of ZIKV infected and noninfected samples. Additionally, it was found that cell adhesion genes that are essential for neurite outgrowth and axon guidance were up-regulated and thereby confirmed the neuronal migration defects observed. This work provided new insights into the underlying mechanisms of CZS and revealed host genes associated with CZS susceptibility.

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“…In an orthotopic glioma model, the live attenuated ZIKV reduced intracerebral tumor growth and prolonged animal survival. In these studies, a selective killing on GSCs within the tumor was observed [26]. Recent findings demonstrate that the entry of ZIKV into GSCs is supported by Integrin α v β 5 because viral entry can be specifically blocked by an α v β 5 -specific antibody or by the cyclic peptide Cilengitide (cyclo-RGDfV-) [27], a peptide that is highly specific for binding to α v integrin [28][29][30].…”

mentioning

confidence: 96%

“…In mice, ZIKV infection prolonged survival by slowing down tumor growth and showed only a weak side effect on normal neural cells [25]. Following these observations, the safety and efficiency of a live attenuated ZIKV candidate was investigated [26]. In an orthotopic glioma model, the live attenuated ZIKV reduced intracerebral tumor growth and prolonged animal survival.…”

mentioning

confidence: 99%

Zikavirus prME Envelope Pseudotyped Human Immunodeficiency Virus Type-1 as a Novel Tool for Glioblastoma-Directed Virotherapy

Kretschmer

Kadlubowska

Hoffmann

et al. 2020

Cancers

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Glioblastoma multiforme is the most lethal type of brain tumor that is not yet curable owing to its frequent resurgence after surgery. Resistance is mainly caused by the presence of a subpopulation of tumor cells, the glioma stem cells (GSCs), which are highly resistant to radiation and chemotherapy. In 2015, Zikavirus (ZIKV)-induced microcephaly emerged in newborns, indicating that ZIKV has a specific neurotropism. Accordingly, an oncolytic tropism for infecting GSCs was demonstrated in a murine tumor model. Like other flaviviruses, ZIKV is enveloped by two proteins, prM and E. The pME expression plasmid along with the HIV-1 vector pNL Luc AM generated prME pseudotyped viral particles. Four different prME envelopes, Z1 to Z4, were cloned, and the corresponding pseudotypes, Z1-to Z4-HIVluc, produced by this two-plasmid system, were tested for entry efficiency using Vero-B4 cells. The most efficient pseudotype, Z1-HIVluc, also infected glioma-derived cell lines U87 and 86HG39. The pseudotype system was then extended by using a three-plasmid system including pME-Z1, the HIV-1 packaging plasmid psPAX2, and the lentiviral vector pLenti-luciferase-P2A-Neo. The corresponding pseudotype, designated Z1-LENTIluc, also infected U87 and 86HG39 cells. Altogether, a pseudotyped virus especially targeting glioma-derived cells might be a promising candidate for a prospective glioblastoma-directed virotherapy. Cancers 2020, 12, 1000 2 of 18 biology, leading to the generation of recombinant, genetically modified virus candidates. Clinical trials have been completed using modified versions of herpes simplex virus [7-12], adenovirus [13,14], Newcastle disease virus [15], reovirus [16,17], parvovirus [18], and poliovirus [19]. Some of these studies demonstrated that a small subset of patients had a benefit from such virotherapy applications, but the statistical significance of these findings must be demonstrated in larger control trials [20].A new discovery, with a high impact on the future aspects of glioma virotherapy, was that Zikavirus (ZIKV) showed a specific neurotropism for glial cells [21]. ZIKV is a new emerging mosquito-borne virus belonging to the Flaviviridae family [22]. In the Flaviviridae family, all members are enveloped viruses with two external, membranous proteins, the envelope E and the precursor of the membrane protein prM [23], both relevant for viral entry. In early 2015, abnormal rates of ZIKV infections were seen in Brazil, and in late 2015, an unexpected high number of newborns showed microcephaly, a disease where a baby's head is much smaller than expected. Altogether, the new emerging ZIKV was shown to be the cause of Guillain-Barré syndrome (GBS), microcephaly, and other congenital brain abnormalities, proving its neurotropic phenotype [24]. An interesting finding was the oncolytic activity of ZIKV against GSCs [25]. A selective effect of ZIKV was observed for GSCs, causing loss of self-renewal and proliferation in glioblastoma organoids. In mice, ZIKV infection prolonged survival by slowing down tumor g...

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Treatment of Human Glioblastoma with a Live Attenuated Zika Virus Vaccine Candidate

Cited by 87 publications

References 38 publications

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

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

The potential role of collagens in congenital Zika syndrome: A systems biology approach

Zikavirus prME Envelope Pseudotyped Human Immunodeficiency Virus Type-1 as a Novel Tool for Glioblastoma-Directed Virotherapy

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