dihydropyridines and Dengue

Flaviviruses, represented by Zika and dengue virus (ZIKV and DENV), are widely present around the world and cause various diseases with serious consequences. However, no antiviral drugs have been clinically approved for use against them. Azelnidipine (ALP) is a dihydropyridine calcium channel blocker and has been approved for use as an antihypertensive drug. In the present study, ALP was found to show potent anti-flavivirus activities in vitro and in vivo. ALP effectively prevented the cytopathic effect induced by ZIKV and DENV and inhibited the production of viral RNA and viral protein in a dose-dependent manner. Moreover, treatment with 0.3 mg/kg of ALP protected 88.89% of mice from lethal challenge. Furthermore, using the time-of-drug-addition assay, the enzymatic inhibition assay, the molecular docking, and the surface plasmon resonance assay, we revealed that ALP acted at the replication stage of the viral infection cycle by targeting the viral RNA-dependent RNA polymerase. These findings highlight the potential for the use of ALP as an antiviral agent to combat flavivirus infections.

Topics: Animals; Antiviral Agents; Azetidinecarboxylic Acid; Dengue; Dihydropyridines; Flavivirus; Flavivirus Infections; Mice; Molecular Docking Simulation; RNA-Dependent RNA Polymerase; Zika Virus; Zika Virus Infection

Severe dengue infection in humans causes a disease characterized by thrombocytopenia, increased levels of cytokines, increased vascular permeability, hemorrhage, and shock. Treatment is supportive. Activation of platelet-activating factor (PAF) receptor (PAFR) on endothelial cells and leukocytes induces increase in vascular permeability, hypotension, and production of cytokines. We hypothesized that activation of PAFR could account for the major systemic manifestations of dengue infection. Inoculation of adult mice with an adapted strain of Dengue virus caused a systemic disease, with several features of the infection in humans. In PAFR(-/-) mice, there was decreased thrombocytopenia, hemoconcentration, decreased systemic levels of cytokines, and delay of lethality, when compared with WT infected mice. Treatment with UK-74,505, an orally active PAFR antagonist, prevented the above-mentioned manifestations, as well as hypotension and increased vascular permeability, and decreased lethality, even when started 5 days after virus inoculation. Similar results were obtained with a distinct PAFR antagonist, PCA-4246. Despite decreased disease manifestation, viral loads were similar (PAFR(-/-)) or lower (PAFR antagonist) than in WT mice. Thus, activation of PAFR plays a major role in the pathogenesis of experimental dengue infection, and its blockade prevents more severe disease manifestation after infection with no increase in systemic viral titers, suggesting that there is no interference in the ability of the murine host to deal with the infection. PAFR antagonists are disease-modifying agents in experimental dengue infection.

Topics: Aedes; Animals; Brain; Cell Line; Cytokines; Dengue; Dengue Virus; Dihydropyridines; Disease Models, Animal; Humans; Imidazoles; Mice; Mice, Inbred BALB C; Platelet Membrane Glycoproteins; Receptors, G-Protein-Coupled; Viral Load