Abstract
Dengue fever is the most widespread of the human arbovirus diseases, with approximately one third of the world's population at risk of infection. Dengue viruses are members of the genus Flavivirus (family Flaviviridae) and, antigenically, they separate as four closely related serotypes (1–4) that share 60–75% amino acid homology. This genetic diversity complicates the process of antiviral drug discovery. Thus, currently no approved dengue-specific therapeutic treatments are available. With the aim of providing an efficient tool for dengue virus drug discovery, a collection of nineteen dengue viruses, representing the genotypic diversity within the four serotypes, was developed. After phylogenetic analysis of the full-length genomes, we selected relevant strains from the EVAg collection at Aix-Marseille University and completed the virus collection, using a reverse genetic system based on the infectious sub-genomic amplicons technique. Finally, we evaluated this dengue virus collection against three published dengue inhibitory compounds. NITD008, which targets the highly conserved active site of the viral NS5 polymerase enzyme, exhibited similar antiviral potencies against each of the different dengue genotypes in the panel. Compounds targeting less conserved protein subdomains, such as the capsid inhibitor ST-148, or SDM25N, a ∂ opioid receptor antagonist which indirectly targets NS4B, exhibited larger differences in potency against the various genotypes of dengue viruses. These results illustrate the importance of a phylogenetically based dengue virus reference panel for dengue antiviral research. The collection developed in this study, which includes such representative dengue viruses, has been made available to the scientific community through the European Virus Archive to evaluate novel DENV antiviral candidates.
Highlights
Dengue virus (DENV) is a major threat to human health, with approximately one third of the world’s population at risk of being infected
DENV is the causative agent of dengue fever, as well as the more severe dengue haemorrhagic fever (DHF)[1] and dengue shock syndrome (DSS)
Dengue is a positive-sense single stranded RNA virus with a 10.7 kb genome encoding a single polyprotein which is post-translationally processed into three structural proteins, viz., capsid (C), pre-membrane, envelope (E) and seven non-structural proteins (NS1, NS2A, NS2B, NS3, NS4A, NS4B and NS5)[4]
Summary
Dengue virus (DENV) is a major threat to human health, with approximately one third of the world’s population at risk of being infected. With the aim of providing a tool for DENV research, with which to assess the antiviral activity of potential inhibitory molecules, we have developed a collection of DENV with sequences that include representative genotypes from within the four DENV serotypes (figure 1). In order to select representative genotypes, we collected dengue full-length genome sequences from the NCBI database and complemented this database with those of our, still unpublished, “in house” and CNR strains.
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