Adenosine triphosphate analogs can efficiently inhibit the Zika virus RNA-dependent RNA polymerase

Hercík, Kamil; Kozák, Jaroslav; Šála, Michal; Dejmek, Milan; Hřebabecký, Hubert; Zborníková, Eva; Smola, Miroslav; Růžek, Daniel; Nencka, Radim; Bouřa, Evžen

doi:10.1016/j.antiviral.2016.11.020

Cited by 66 publications

(43 citation statements)

References 30 publications

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“…In addition, a primer dependent activity was also recently described using a homopolymeric template 12 or a short template/primer system corresponding to the 5′ end of the genome as primer and the 3′ end of the antigenome as template 11 . In parallel, Hercik and collaborators described the purification of the ZIKV NS5 with both the MTase domain and RdRp domain leading to a Mg-dependent activity 10 . However, the substrate used was different [a poly(rU) template with an oligo(rA) primer] and bypassed the de novo initiation expected for flavivirus polymerases.…”

Section: Discussionmentioning

confidence: 99%

“…Our work demonstrates that the isolated ZIKV RdRp domain can be used in vitro to evaluate specific compounds and will help the repositioning of already approved drugs able to inhibit other viral polymerases. A potential lead could be molecules developed against the HCV NS5B protein such as sofosbuvir and other 2′-C-methylated nucleosides that have recently been shown to be active against ZIKV NS5 in vitro or the ZIKV replication in Vero cell 10, 14, 19, 20 . However, in silico studies performed on the ZIKV polymerase have predicted that most HCV NS5B inhibitors could be active against ZIKV 21 .…”

Section: Discussionmentioning

confidence: 99%

“…Only recently Hercik et al . described the purification of a ZIKV full-length NS5 protein (MTase and RdRp domains) 10 . In this study, the full-length NS5 was capable of an uncharacterized nucleotide incorporation using a primed template enabling the authors to test nucleoside analog inhibitors.…”

Section: Introductionmentioning

confidence: 99%

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De novo RNA synthesis catalyzed by the Zika Virus RNA polymerase domain

Calmels

Ventura

Aknin

et al. 2017

Sci Rep

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Mosquito- and tick-borne pathogens including Chikungunya, Dengue, Japanese encephalitis, West Nile, Yellow fever and Zika virus, represent a new economic and public health challenge. In the absence of effective vaccines and specific therapies, only supportive regimens are administrated for most of these infections. Thus, the development of a targeted therapy is mandatory to stop the rapid progression of these pathogens and preoccupant associated burdens such as Guillain-Barre syndrome, microcephaly. For this, it is essential to develop biochemical tools to help study and target key viral enzymes involved in replication such as helicase complexes, methyl-transferases and RNA-dependent RNA polymerases. Here, we show that a highly purified ZIKV polymerase domain is active in vitro. Importantly, we show that this isolated domain is capable of de novo synthesis of the viral genome and efficient elongation without terminal nucleotide transferase activity. Altogether, this isolated polymerase domain will be a precious tool to screen and optimize specific nucleoside and non-nucleoside inhibitors to fight against Zika infections.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

De novo RNA synthesis catalyzed by the Zika Virus RNA polymerase domain

Calmels

Ventura

Aknin

et al. 2017

Sci Rep

View full text Add to dashboard Cite

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“…The serum half-life of 7d2CMA, however, is markedly longer (0.3 vs. 1.6 hr (58)). Interestingly, 7d2CMA shows an EC50 against Zika virus in cultured mammalian cells of about 10 µM, and dosing regimens have shown significant inhibition in animal models (59,60). This suggests it might likewise be possible to achieve inhibition of LRV1 in vivo using 7d2CMA.…”

Section: Discussionmentioning

confidence: 99%

Concentration of 2′C-methyladenosine triphosphate by Leishmania guyanensis enables specific inhibition of Leishmania RNA virus 1 via its RNA polymerase

Robinson

Beverley

2018

Journal of Biological Chemistry

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Leishmania is a widespread trypanosomatid protozoan parasite causing significant morbidity and mortality in humans. The endobiont dsRNA virus Leishmania RNA virus 1 (LRV1) chronically infects some strains, where it increases parasite numbers and virulence in murine leishmaniasis models, and correlates with increased treatment failure in human disease. Previously, we reported that 2'-C-methyladenosine (2CMA) potently inhibited LRV1 in Leishmania guyanensis (Lgy) and L. braziliensis, leading to viral eradication at concentrations above 10 µM. Here we probed the cellular mechanisms of 2CMA inhibition, involving metabolism, accumulation and inhibition of the viral RNA dependent RNA polymerase (RDRP) . Activation to 2CMA triphosphate (2CMA-TP) was required, as 2CMA showed no inhibition of RDRP activity from virions purified on cesium chloride gradients. In contrast, 2CMA-TP showed IC50s ranging from 150 to 910 µM, depending on the CsCl density of the virion (empty, ssRNA-and dsRNA-containing). Lgy parasites incubated in vitro with 10 µM 2CMA accumulated 2CMA-TP to 410 µM, greater than the most sensitive RDRP IC50 measured. Quantitative modeling showed good agreement between the degree of LRV1 RDRP inhibition and LRV1 levels. These results establish that 2CMA activity is due to its conversion to 2CMA-TP, which accumulates to levels that inhibit RDRP and cause LRV1 loss. This attests to the impact of the Leishmania purine uptake and metabolism pathways, which allow even a weak RDRP inhibitor to effectively eradicate LRV1 at micromolar concentrations. Future RDRP inhibitors with increased potency may have potential therapeutic applications for ameliorating the increased Leishmania pathogenicity conferred by LRV1.

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“…Bir başka çalışma-da, sofosbuvirin multiple insan tümör hücrelerinde ve insan nöronal sistem hücre dizilerinde Zika virus enfeksiyonlarını ve viral replikasyonu inhibe ettiği gösterilmiştir (48) . Yakın zamanda, adenozin trifosfat analoglarının Zika virusun RNA bağımlı RNA polimerazını etkili bir şekilde inhibe ettiğini ve flavonoidlerin Zika virus NS2B-NS3 proteazı üzerine inhibitör etkisi olduğunu gösteren çalışma-lar da yayımlanmıştır (49,50) .…”

Section: Tedaviunclassified