Nucleoside Inhibitors of Zika Virus

Eyer, Luděk; Nencka, Radim; Huvarová, Ivana; Palus, Martin; Alves, Maria João; Gould, Ernest A.; Clercq, Erik De; Růžek, Daniel

doi:10.1093/infdis/jiw226

Cited by 152 publications

(141 citation statements)

References 13 publications

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“…Another recent publication, by Eyer et al, indicated that a 50 M concentration of sofosbuvir cannot inhibit Zika virus replication in Vero cell culture (38). In the last study, the authors also showed that 2=-C-methylated nucleosides are more potent inhibitors of ZIKV replication in Vero cell culture, which agrees well with our results of relatively low discrimination for 2=-C-methylated ribonucleotides by ZIKV polymerase.…”

Section: Discussionsupporting

confidence: 92%

Analysis of Ribonucleotide 5′-Triphosphate Analogs as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase by Using Nonradioactive Polymerase Assays

Bluemling

Collop

et al. 2017

Antimicrob Agents Chemother

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Zika virus (ZIKV) is an emerging human pathogen that is spreading rapidly through the Americas and has been linked to the development of microcephaly and to a dramatically increased number of Guillain-Barré syndrome cases. Currently, no vaccine or therapeutic options for the prevention or treatment of ZIKV infections exist. In the study described in this report, we expressed, purified, and characterized full-length nonstructural protein 5 (NS5) and the NS5 polymerase domain (NS5pol) of ZIKV RNA-dependent RNA polymerase. Using purified NS5, we developed an in vitro nonradioactive primer extension assay employing a fluorescently labeled primertemplate pair. Both purified NS5 and NS5pol can carry out in vitro RNA-dependent RNA synthesis in this assay. Our results show that Mn 2ϩ is required for enzymatic activity, while Mg 2ϩ is not. We found that ZIKV NS5 can utilize single-stranded DNA but not double-stranded DNA as a template or a primer to synthesize RNA. The assay was used to compare the efficiency of incorporation of analog 5=-triphosphates by the ZIKV polymerase and to calculate their discrimination versus that of natural ribonucleotide triphosphates (rNTPs). The 50% inhibitory concentrations for analog rNTPs were determined in an alternative nonradioactive coupled-enzyme assay. We determined that, in general, 2=-C-methyl-and 2=-C-ethynyl-substituted analog 5=-triphosphates were efficiently incorporated by the ZIKV polymerase and were also efficient chain terminators. Derivatives of these molecules may serve as potential antiviral compounds to be developed to combat ZIKV infection. This report provides the first characterization of ZIKV polymerase and demonstrates the utility of in vitro polymerase assays in the identification of potential ZIKV inhibitors.

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Section: Discussionsupporting

confidence: 92%

Analysis of Ribonucleotide 5′-Triphosphate Analogs as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase by Using Nonradioactive Polymerase Assays

Bluemling

Collop

et al. 2017

Antimicrob Agents Chemother

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“…These compounds provide a basis for structure-based optimization and rational design of effective prodrugs, which will be further tested in rodent models for therapy of ZIKV infection. 84 …”

Section: -82mentioning

confidence: 99%

Antiviral Nucleoside and Nucleotide Analogs: A Review

Mahmoud

Hasabelnaby

Hammad

et al. 2018

Journal of Advanced Pharmacy Research

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Virus infections are an increasing and probably lasting global risk. Nucleoside and nucleotide analogs represent the largest class of antiviral drugs. Early success in the treatment of human immunodeficiency virus infection and the recent approval of sofosbuvir as phosphoramidate nucleoside prodrug for chronic hepatitis C have provided proof of concept for important this class of compounds as an antiviral agent. This review summarizes the antiviral activity of nucleoside and nucleotide analogs and their recent application.

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“…For instances, different nucleoside analogs/derivatives that target viral polymerases, such as 2 -C-methylated nucleosides, have shown to inhibit ZIKV multiplication in cell culture (Eyer et al, 2016;Zmurko et al, 2016;Hercik et al, 2017), as did Sofosbuvir and BCX4430 (Bullard-Feibelman et al, 2017;Julander et al, 2017;Sacramento et al, 2017), which also induced greater survival rates in treated experimental immunodeficient mice (Bullard-Feibelman et al, 2017;Julander et al, 2017). Likewise, the pyrimidine synthesis inhibitors NITD008, CID 91632869, finasteride, brequinar, 6-azauridine, gemcitabine, and 5-fluorouracil reduced viral multiplication to different levels (Pascoalino et al, 2016;Adcock et al, 2017;Kuivanen et al, 2017).…”

Section: Antiviralsmentioning

confidence: 99%

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

2018

Frontiers Research Topics

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Zika is a viral disease transmitted mainly by mosquitoes of the genus Aedes. In recent years, it has expanded geographically, changing from an endemic mosquito-borne disease across equatorial Asia and Africa, to an epidemic disease causing large outbreaks in several areas of the world. With the recent Zika virus (ZIKV) outbreaks in the Americas, the disease has become a focus of attention of public health agencies and of the international research community, especially due to an association with neurological disorders in adults and to the severe neurological and ophthalmological abnormalities found in fetuses and newborns of mothers exposed to ZIKV during pregnancy. A large number of studies have been published in the last 3 years, revealing the structure of the virus, how it is transmitted and how it affects human cells. Many different animal models have been developed, which recapitulate several features of ZIKV disease and its neurological consequences. Moreover, several vaccine candidates are now in active preclinical development, and three of them have already entered phase I clinical trials. Likewise, many different compounds targeting viral and cellular components are being tested in in vitro and in experimental animal models. This review aims to discuss the current state of this rapidly growing literature from a multidisciplinary perspective, as well as to present an overview of the public health response to Zika and of the perspectives for the prevention and treatment of this disease.

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Nucleoside Inhibitors of Zika Virus

Cited by 152 publications

References 13 publications

Analysis of Ribonucleotide 5′-Triphosphate Analogs as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase by Using Nonradioactive Polymerase Assays

Analysis of Ribonucleotide 5′-Triphosphate Analogs as Potential Inhibitors of Zika Virus RNA-Dependent RNA Polymerase by Using Nonradioactive Polymerase Assays

Antiviral Nucleoside and Nucleotide Analogs: A Review

Zika Virus: What Have We Learnt Since the Start of the Recent Epidemic?

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