Abstract
BackgroundDengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. In a previous screening assay, we identified a group of N-allyl acridones as effective virus inhibitors. Here, the antiviral activity and mode of action targeted to viral RNA replication of one of the most active DENV-2 inhibitors was further characterized.ResultsThe compound 10-allyl-7-chloro-9(10H)-acridone, designated 3b, was active to inhibit the in vitro infection of Vero cells with the four DENV serotypes, with effective concentration 50% (EC50) values in the range 12.5-27.1 μM, as determined by virus yield inhibition assays. The compound was also effective in human HeLa cells. No cytotoxicity was detected at 3b concentrations up to 1000 μM. Mechanistic studies demonstrated that virus entry into the host cell was not affected, whereas viral RNA synthesis was strongly inhibited, as quantified by real time RT-PCR. The addition of exogenous guanosine together with 3b rescued only partially the infectivity of DENV-2.ConclusionsThe acridone derivative 3b selectively inhibits the infection of Vero cells with the four DENV serotypes without a direct interaction with the host cell or the virion but interfering specifically with the intracellular virus multiplication. The mode of antiviral action for this acridone apparently involves the cellular enzyme inosine-monophospahe dehydrogenase together with another still unidentified target related to DENV RNA synthesis.
Highlights
Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes
In a previous screening assay of antiviral activity against DENV-2 of a series of N-substituted acridones, we identified a group of N-allyl derivatives as effective virus inhibitors [21]
Spectrum of anti-DENV activity The antiviral activity of 3b against DENV-2 was evaluated by a virus yield reduction assay in Vero cells
Summary
Dengue virus (DENV), a member of the family Flaviviridae, is at present the most widespread causative agent of a human viral disease transmitted by mosquitoes. Despite the increasing incidence of this pathogen, there are no antiviral drugs or vaccines currently available for treatment or prevention. The World Health Organization estimates that DENV infects annually 50 million people around the world causing a wide range of clinical disease, from the benign and autolimited dengue fever to the severe forms of dengue hemorrhagic fever and dengue shock syndrome [1,2]. No specific anti-DENV drugs or vaccines are currently available. The present treatment for DENV infected patients consists only in supportive medical care directed to reduce the symptoms and to improve survival in the severe forms of disease. The candidate drugs just tested in humans include the lysosomotropic agent chloroquine [7] and the polymerase inhibitor balapiravir [8], both without therapeutic efficacy, whereas trials of lovastatin, a cholesterol-reducing agent, and cellular glucosidase inhibitors are currently underway [9,10]
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