Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus

Rausch, Keiko; Hackett, Brent A.; Weinbren, Nathan L.; Reeder, Sophia; Sadovsky, Yoel; Hunter, Christopher A.; Schultz, D.; Coyne, Carolyn B.; Cherry, Sara

doi:10.1016/j.celrep.2016.12.068

Cited by 155 publications

(153 citation statements)

References 43 publications

(57 reference statements)

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“…During the preparation of this work, AR-12 and a few other kinase inhibitors were recently identified to exhibit in vitro anti-ZIKV activity in human osteosarcoma (U2OS) cells in a drug screening programme (Rausch et al, 2017). However, no further validation of this preliminary finding in other clinically relevant cell lines or suitable animal model was reported, and the anti-ZIKV mechanism of AR-12 was not investigated.…”

Section: Discussionmentioning

confidence: 99%

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

et al. 2018

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A B S T R A C TZika virus (ZIKV) is a human-pathogenic flavivirus that has recently emerged as a global public health threat. ZIKV infection may be associated with congenital malformations in infected fetuses and severe neurological and systemic complications in infected adults. There are currently limited treatment options for ZIKV infection. AR-12 (OSU-03012) is a celecoxib derivative cellular kinase inhibitor that has broad-spectrum antiviral activities. In this study, we investigated the antiviral activity and mechanism of AR-12 against ZIKV. We evaluated the in vitro anti-ZIKV activity of AR-12, using cell protection and virus yield reduction assays, in multiple clinically relevant cell lines, and the in vivo treatment effects of AR-12 in a lethal mouse model using type I interferon receptordeficient A129 mice. AR-12 inhibited ZIKV strains belonging to both the African and Asian/American lineages in Huh-7 and/or neuronal cells. AR12's IC 50 against ZIKV was consistently < 2 μM in these cells. ZIKV-infected A129 mice treated with intraperitoneally or orally administered AR-12 had significantly higher survival rate (50.0%-83.3% vs 0%, P < 0.05), less body weight loss, and lower blood and tissue ZIKV RNA loads than untreated control A129 mice. These anti-ZIKV effects were likely the results of down-regulation of the PI3K/Akt pathway by AR-12. Clinical trials using the clinically available and broad-spectrum AR-12 as an empirical treatment should be considered especially for patients residing in or returning from areas endemic of ZIKV and other arboviral infections who present with an acute undifferentiated febrile illness.

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Section: Discussionmentioning

confidence: 99%

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

et al. 2018

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“…For example, repurposing FDA-approved drugs is a valuable strategy to identify new antivirals with acceptable toxicity and a potential fast path to the clinic (Barrows et al, 2016; Xu et al, 2016). Furthermore, natural products can exhibit antiviral activity (Estoppey et al, 2017; Rausch et al, 2017). Recently, the fungal compound cavinafungin was shown to be potent and selectively active against DENV and ZIKV (Estoppey et al, 2017).…”

Section: Discussionmentioning

confidence: 99%

A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity

et al. 2017

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Summary The mosquito-borne flaviviruses include important human pathogens such as dengue, Zika, West Nile and yellow fever virus, which pose a serious threat for global health. Recent genetic screens identified ER-membrane multiprotein complexes including the oligosaccharyltransferase (OST) complex as critical flavivirus host factors. Here, we show that a chemical modulator of the OST complex termed NGI-1 has promising antiviral activity against flavivirus infections. We demonstrate that NGI-1 blocks viral RNA replication, and that antiviral activity does not depend on inhibition of the N-glycosylation function of the OST. Viral mutants adapted to replicate in cells deficient of the OST complex showed resistance to NGI-1 treatment reinforcing the on-target activity of NGI-1. Lastly, we show that NGI-1 also has strong antiviral activity in primary and disease-relevant cell types. This study provides an example for advancing from the identification of genetic determinants of infection to a host-directed antiviral compound with broad activity against flaviviruses.

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“…HUVEC and hUtMEC were purchased from Lonza and cultured as described previously (Rausch et al, 2017). Cells were inoculated with ZIKV (Paraiba 2015; MOI of 3) for 48 h following a 16 h treatment with 100 ng/mL of recombinant IFN-β, IFN-λ1 or IFN-λ3 (R&D Systems).…”

Section: Star Methodsmentioning

confidence: 99%

Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero

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et al. 2017

Cell Host & Microbe

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SUMMARY Although Zika virus (ZIKV)-induced congenital disease occurs more frequently during early stages of pregnancy, its basis remains undefined. Using established type I interferon (IFN)-deficient mouse models of ZIKV transmission in utero, we found that the placenta and fetus were more susceptible to ZIKV infection at earlier gestational stages. Whereas ZIKV infection at embryonic day 6 (E6) resulted in placental insufficiency and fetal demise, infections at midstage (E9) resulted in reduced cranial dimensions, and infection later in pregnancy (E12) caused no apparent fetal disease. In addition, we found that fetuses lacking type III IFN-λ signaling had increased ZIKV replication in the placenta and fetus when infected at E12, and reciprocally, treatment of pregnant mice with IFN-λ2 reduced ZIKV infection. IFN-λ treatment analogously diminished ZIKV infection in human midgestation fetal- and maternal-derived tissue explants. Our data establish a model of gestational stage-dependence of ZIKV pathogenesis and IFN-λ-mediated immunity at the maternal-fetal interface.

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Screening Bioactives Reveals Nanchangmycin as a Broad Spectrum Antiviral Active against Zika Virus

Cited by 155 publications

References 43 publications

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

The celecoxib derivative kinase inhibitor AR-12 (OSU-03012) inhibits Zika virus via down-regulation of the PI3K/Akt pathway and protects Zika virus-infected A129 mice: A host-targeting treatment strategy

A Small-Molecule Oligosaccharyltransferase Inhibitor with Pan-flaviviral Activity

Gestational Stage and IFN-λ Signaling Regulate ZIKV Infection In Utero

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