BCX4430, a Novel Nucleoside Analog, Effectively Treats Yellow Fever in a Hamster Model

Julander, Justin G.; Bantia, Shanta; Taubenheim, Brian R.; Minning, Dena M.; Kotian, Pravin L.; Morrey, John D.; Smee, Donald F.; Sheridan, William; Babu, Y.S.

doi:10.1128/aac.03368-14

Cited by 86 publications

(80 citation statements)

References 20 publications

(29 reference statements)

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“…BCX4430 is a broad-spectrum antiviral that is potently active against a wide variety of RNA viruses including YFV, EBOV and MARV in animal models (Julander et al, 2014; Warren et al, 2014). The efficacy of BCX4430 in a lethal ZIKV infection described herein represents the first time that protection from ZIKV-associated mortality has been demonstrated in a mouse model.…”

Section: Discussionmentioning

confidence: 99%

“…Broad-spectrum activity against various RNA viruses in cell culture has been reported (Warren et al, 2014). BCX4430 is highly active in a hamster model of yellow fever virus (YFV) disease, with efficacy demonstrated even when administered once viremia and hepatitis were established (Julander et al, 2014). Potent activity has also been reported in a mouse models of Ebola (EBOV) and Marburg virus (MARV) diseases, and a lethal non-human primate model of MARV disease (Warren et al, 2014).…”

Section: Introductionmentioning

confidence: 99%

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Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model

et al. 2017

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Zika virus (ZIKV) is currently undergoing pandemic emergence. While disease is typically subclinical, severe neurologic manifestations in fetuses and newborns after congenital infection underscore an urgent need for antiviral interventions. The adenosine analog BCX4430 has broad-spectrum activity against a wide range of RNA viruses, including potent in vivo activity against yellow fever, Marburg and Ebola viruses. We tested this compound against African and Asian lineage ZIKV in cytopathic effect inhibition and virus yield reduction assays in various cell lines. To further evaluate the efficacy in a relevant animal model, we developed a mouse model of severe ZIKV infection, which recapitulates various human disease manifestations including peripheral virus replication, conjunctivitis, encephalitis and myelitis. Time-course quantification of viral RNA accumulation demonstrated robust viral replication in several relevant tissues, including high and persistent viral loads observed in the brain and testis. The presence of viral RNA in various tissues was confirmed by an infectious culture assay as well as immunohistochemical staining of tissue sections. Treatment of ZIKV-infected mice with BCX4430 significantly improved outcome even when treatment was initiated during the peak of viremia. The demonstration of potent activity of BCX4430 against ZIKV in a lethal mouse model warrant its continued clinical development.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model

et al. 2017

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“…Antiviral compounds selected for the study include 6-azauridine (Flint et al, 2014; Rada and Dragun, 1977; Smee et al, 1987), BCX4430 (Julander et al, 2014; Taylor et al, 2016), 3-deazaguanine (Allen et al, 1977; Smee et al, 2016), EICAR (De Clercq, 2015; De Clercq et al, 1991), favipiravir (Furuta et al, 2013; Mendenhall et al, 2011), Infergen™ (interferon alfacon 1, hereafter referred to as infergen) (Julander et al, 2007; Morrey et al, 2004), mycophenolic acid (Cline et al, 1969; Takhampunya et al, 2006; To et al, 2016), ribavirin (Sidwell et al, 1972; Smee et al, 1987; Westover et al, 2016), and tiazofurin (Baker et al, 2003; Huggins et al, 1984). All of the compounds have antiviral properties, but against different viruses.…”

Section: Introductionmentioning

confidence: 99%

Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties

Smee

Hurst

Evans

et al. 2017

Journal of Virological Methods

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Studies were conducted to determine the performance of four dyes in assessing antiviral activities of compounds against three RNA viruses with differing cytopathogenic properties. Dyes included alamarBlue® measured by absorbance (ALB-A) and fluorescence (ALB-F), neutral red (NR), Viral ToxGlo™ (VTG), and WST-1. Viruses were chikungunya, dengue type 2, and Junin, which generally cause 100, 80-90, and 50% maximal cytopathic effect (CPE), respectively, in Vero 76. Compounds evaluated were 6-azauridine, BCX-4430, 3-deazaguanine, EICAR, favipiravir, infergen, mycophenolic acid (MPA), ribavirin, and tiazofurin. The 50% virus-inhibitory (EC50) values for each inhibitor and virus combination did not vary significantly based on the dye used. However, dyes varied in distinguishing the vitality of virus-infected cultures when not all cells were killed by virus infection. For example, VTG uptake into dengue-infected cells was nearly 50% when visual examination showed only 10-20% cell survival. ALB-A measured infected cell viability differently than ALB-F as follows: 16% versus 32% (dengue-infected), respectively, and 51% versus 72% (Junin-infected), respectively. Cytotoxicity (CC50) assays with dyes in uninfected proliferating cells produced similar CC50 values for EICAR (1.5-8.9 μM) and MPA (0.8-2.5 μM). 6-Azauridine toxicity was 6.1-17.5 μM with NR, VTG, and WST-1, compared to 48-92 μM with ALB-A and ALB-F.(P<0.001). Curiously, the CC50 values for 3-deazaguanine were 83-93 μM with ALB-F versus 2.4-7.0 μM with all other dyes including ALB-A (P<0.001). Overall, ALB minimized the toxicities detected with these two inhibitors. Because the choice of dyes affected CC50 values, this impacted on the resulting in vitro selectivity indexes (calculated as CC50/EC50 ratio).

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“…However, only a few of these compounds have shown protection in animal models of EBOV, which is a critical step for screening potential drug candidates for future human clinical trials (3,5,6). One class of compounds that has emerged with many promising antiviral candidates is the group of flavonoid molecules.…”

mentioning

confidence: 99%

Prophylactic Efficacy of Quercetin 3-β- O - d -Glucoside against Ebola Virus Infection

Qiu

Kroeker

et al. 2016

Antimicrob Agents Chemother

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Ebola outbreaks occur on a frequent basis, with the 2014-2015 outbreak in West Africa being the largest one ever recorded. This outbreak has resulted in over 11,000 deaths in four African countries and has received international attention and intervention. Although there are currently no approved therapies or vaccines, many promising candidates are undergoing clinical trials, and several have had success in promoting recovery from Ebola. However, these prophylactics and therapeutics have been designed and tested only against the same species of Ebola virus as the one causing the current outbreak. Future outbreaks involving other species would require reformulation and possibly redevelopment. Therefore, a broad-spectrum alternative is highly desirable. We have found that a flavonoid derivative called quercetin 3-␤-O-D-glucoside (Q3G) has the ability to protect mice from Ebola even when given as little as 30 min prior to infection. Furthermore, we have demonstrated that this compound targets the early steps of viral entry. Most promisingly, antiviral activity against two distinct species of Ebola virus was seen. This study serves as a proof of principle that Q3G has potential as a prophylactic against Ebola virus infection.

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BCX4430, a Novel Nucleoside Analog, Effectively Treats Yellow Fever in a Hamster Model

Cited by 86 publications

References 20 publications

Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model

Efficacy of the broad-spectrum antiviral compound BCX4430 against Zika virus in cell culture and in a mouse model

Evaluation of cell viability dyes in antiviral assays with RNA viruses that exhibit different cytopathogenic properties

Prophylactic Efficacy of Quercetin 3-β- O - d -Glucoside against Ebola Virus Infection

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