A Screen of FDA-Approved Drugs for Inhibitors of Zika Virus Infection

Barrows, Nicholas J.; Campos, Rafael K.; Powell, Steven T.; Prasanth, K. Reddisiva; Schott-Lerner, Geraldine; Soto-Acosta, Rubén; Galarza-Muñoz, Gaddiel; McGrath, Erica L.; Urrabaz‐Garza, Rheanna; Gao, Junling; Wu, Ping; Menon, Ramkumar; Saade, George R.; Fernández‐Salas, Ildefonso; Rossi, Shannan L.; Vasilakis, Nikos; Routh, Andrew; Bradrick, Shelton S.; García-Blanco, Mariano A.

doi:10.1016/j.chom.2016.07.004

Cited by 462 publications

(433 citation statements)

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“…Although development of a vaccine could provide a long-term solution to the current ZIKV epidemic, there remains an unmet clinical need to identify drugs that can limit or prevent the consequences of congenital infection. A recent screen of a subset of Food and Drug Administration (FDA)-approved compounds against ZIKV in hepatic cells identified several anticancer, antimicrobial, antiparasitic, and antifungal drugs with anti-ZIKV activity (10). Another screen, based on human neural progenitor cells, identified an antifungal drug and Significance Zika virus (ZIKV) is a mosquito-borne flavivirus that has rapidly spread through the Americas and has been associated with fetal abnormalities, including microcephaly.…”

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confidence: 99%

“…However, the majority of compounds with anti-ZIKV activity from these screens are contraindicated or of unknown safety during pregnancy. Furthermore, two promising candidates that might be safe during pregnancy, daptomycin and sofosbuvir, showed variable effectiveness by cell type (7,10,12). Combining unbiased screens of approved compounds with comparisons of top candidates with known antiviral activity may quickly narrow the search for drugs that could mitigate the effects of congenital ZIKV infection.…”

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confidence: 99%

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Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Retallack

Lullo

Arias

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

463

393

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The rapid spread of Zika virus (ZIKV) and its association with abnormal brain development constitute a global health emergency. Congenital ZIKV infection produces a range of mild to severe pathologies, including microcephaly. To understand the pathophysiology of ZIKV infection, we used models of the developing brain that faithfully recapitulate the tissue architecture in early to midgestation. We identify the brain cell populations that are most susceptible to ZIKV infection in primary human tissue, provide evidence for a mechanism of viral entry, and show that a commonly used antibiotic protects cultured brain cells by reducing viral proliferation. In the brain, ZIKV preferentially infected neural stem cells, astrocytes, oligodendrocyte precursor cells, and microglia, whereas neurons were less susceptible to infection. These findings suggest mechanisms for microcephaly and other pathologic features of infants with congenital ZIKV infection that are not explained by neural stem cell infection alone, such as calcifications in the cortical plate. Furthermore, we find that blocking the glia-enriched putative viral entry receptor AXL reduced ZIKV infection of astrocytes in vitro, and genetic knockdown of AXL in a glial cell line nearly abolished infection. Finally, we evaluate 2,177 compounds, focusing on drugs safe in pregnancy. We show that the macrolide antibiotic azithromycin reduced viral proliferation and virusinduced cytopathic effects in glial cell lines and human astrocytes. Our characterization of infection in the developing human brain clarifies the pathogenesis of congenital ZIKV infection and provides the basis for investigating possible therapeutic strategies to safely alleviate or prevent the most severe consequences of the epidemic.A correlation between congenital exposure to the mosquitoborne and sexually transmitted Zika flavivirus (ZIKV) and the increased incidence of severe microcephaly suggests a causal relationship between ZIKV infection and neurodevelopmental abnormalities (1, 2). However, the mechanisms of infection and specifically which cell populations are vulnerable to ZIKV during the course of human brain development remain unclear. Major insights have been drawn from in vitro models of human brain development and primary mouse tissues. In the developing mouse brain, ZIKV has been shown to infect radial glia and neurons (3), whereas studies in human pluripotent stem cell (hPSC)-derived neural cells have highlighted widespread infection and apoptosis of neural progenitor cells (4,5). Because these models do not fully recapitulate the developmental events and cell types present during human brain development, these results may not faithfully represent ZIKV-induced pathology in vivo.During human brain development, radial glial cells, the neural stem cells, give rise to diverse types of neuronal and glial cells, including neurons, oligodendrocytes, and astrocytes, in a temporally controlled pattern. We reasoned that identifying cell types that are especially vulnerable to viral infection wou...

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mentioning

confidence: 99%

mentioning

confidence: 99%

Zika virus cell tropism in the developing human brain and inhibition by azithromycin

Retallack

Lullo

Arias

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

463

393

View full text Add to dashboard Cite

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“…The ability to culture and manipulate hNSCs provides a critical tool that can be used for a variety of purposes from modeling human disease to high throughput drug screening. [6][7][10][11][12] One of the challenges with hNSC culture is maintaining the "stemness" of the culture. Svendsen et al developed a method in 1998 to maintain primary human fetal neural stem cells in culture by chopping neurospheres into pieces.…”

Section: Discussionmentioning

confidence: 99%

“…Culture of these cells has been used in multiple studies ranging from infectious disease to amyotrophic lateral sclerosis. [5][6][7] This system is particularly powerful if multiple donors can be found as individual differences can be evaluated. However, the technical challenges associated with effect and reproducible hNSC culture still present a barrier in the field.…”

Section: Introductionmentioning

confidence: 99%

Proliferation and differentiation of human fetal brain neural stem cells in vitro

McGrath¹,

Gao²,

Wu³

2018

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Primary human fetal brain neural stem cells (hNSCs) are a unique non-genetically modified model system to study molecular mechanisms underlying human neural development, to model human diseases, and to screen drugs or validate new treatments. They may also be used for cell transplantation to treat various neurological diseases. This protocol details our methods that can be used to expand hNSCs in culture as well as how to differentiate them into various neuronal lineages and astrocytes.

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“…Daptomycin is a lipopeptide antibiotic that inserts into cell membranes rich in Phosphatidylglycerol (PG), and impacts PG-rich late endosomal membranes, which are critical for viral entry. Daptomycin showed variable effectiveness in reducing ZIKV replication in various human cell types [83,84]. Azithromycin, a macrolide antibiotic, has been shown to prevent ZIKV from infecting fetal brain tissue cells in vitro [84].…”

Section: Antibiotics and Their Anti-zikv Activitymentioning

confidence: 99%