Nucleobases and corresponding nucleosides display potent antiviral activities against dengue virus possibly through viral lethal mutagenesis.

Li Qiu,Steven E Patterson,Robert J Geraghty,Laurent F Bonnac,Adly M M Abd-Alla

doi:10.1371/journal.pntd.0006421

Abstract

Dengue virus affects millions of people worldwide each year. To date, there is no drug for the treatment of dengue-associated disease. Nucleosides are effective antivirals and work by inhibiting the accurate replication of the viral genome. Nucleobases offer a cheaper alternative to nucleosides for broad antiviral applications. Metabolic activation of nucleobases involves condensation with 5-phosphoribosyl-1-pyrophosphate to give the corresponding nucleoside-5’-monophosphate. This could provide an alternative to phosphorylation of a nucleoside, a step that is often rate limiting and inefficient in activation of nucleosides. We evaluated more than 30 nucleobases and corresponding nucleosides for their antiviral activity against dengue virus. Five nucleobases and two nucleosides were found to induce potent antiviral effects not previously described. Our studies further revealed that nucleobases were usually more active with a better tissue culture therapeutic index than their corresponding nucleosides. The development of viral lethal mutagenesis, an antiviral approach that takes into account the quasispecies behavior of RNA viruses, represents an exciting prospect not yet studied in the context of dengue replication. Passage of the virus in the presence of the nucleobase 3a (T-1105) and corresponding nucleoside 3b (T-1106), favipiravir derivatives, induced an increase in apparent mutations, indicating lethal mutagenesis as a possible antiviral mechanism. A more concerted and widespread screening of nucleobase libraries is a very promising approach to identify dengue virus inhibitors including those that may act as viral mutagens.

Highlights

Dengue virus (DENV) is a worldwide health threat, with hundreds of millions of people infected yearly in more than 100 countries [1]
Nucleosides must be converted within the cell to their triphosphate form to inhibit virus replication, inefficient phosphorylation often leads to suboptimal activity
We identified some known and previously undescribed dengue virus nucleobase inhibitors and their corresponding nucleosides

Summary

Introduction

Dengue virus (DENV) is a worldwide health threat, with hundreds of millions of people infected yearly in more than 100 countries [1]. An error-prone viral polymerase combined with a high replication rate are considered to be the main sources of mutations It is this critical source of viral adaptability (e.g. the virus high mutation rate) that makes RNA viruses a target of choice for antiviral lethal mutagenesis strategies [15,16,17]. RNA viruses maintain a delicate balance between their need to adapt and their need to preserve a level of genetic integrity put at risk by deleterious mutations [18] Modifying this fragile equilibrium by increasing the viral mutation rate with mutagens has been proposed as an antiviral strategy [15]. The well-known antiviral nucleoside drug ribavirin induces lethal mutagenesis for different viruses [19,20,21,22]

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Discussion

Conclusion