Antiviral activity of anisomycin against dengue and Zika viruses

DAMONTE, E.B.; BRUNETTI, J.E.; QUINTANA, V.M.; JULANDER, J.

Galveston

Congreso; VI Pan American Dengue Research Network Meeting; 2018

We investigated the antiviral activity of anisomycin, an alkaloid produced by Streptomyces griseolus, against dengue (DENV) and Zika (ZIKV) viruses. We first examined the effect of anisomycin on cell viability in Vero, A549, HepG2 and U937 cell lines using an MTS assay. The effect of non-cytotoxic concentrations of anisomycin on viral multiplication was analyzed using a virus yield inhibition assay. Anisomycin caused a dose dependent inhibition of viral production in Vero cells, with 50% effective concentration values of 23.2, 31.3, 24.8, 61.6 and 33.0 nM for DENV-1, DENV-2, DENV-3, DENV-4 and ZIKV, respectively. A 99.99% inhibition of DENV-2 yield was observed at the highest concentration of anisomycin (200nM) even at a multiplicity of infection of 50 PFU/cell. The compound exhibited antiviral activity against clinical isolates of DENV and against DENV-2 grown in several different human cell lines. Both the kinetics of DENV-2 entry and uncoating were not affected by the compound. However, a strong inhibition of DENV-2 protein expression and viral RNA synthesis was demonstrated. The toxicity and antiviral activity of anisomycin was evaluated in a mouse model of ZIKV morbidity and mortality. Doses up to 100 mg/kg/d were well-tolerated. Mice were treated with anisomycin (4, 20, or 100 mg/kg/d) for 10 days beginning 4 h after ZIKV infection. Viremia on day 5, weight change between 0 and 21 dpi and survival through 28 dpi were used as primary endpoints. The results obtained suggest a reverse dose response, since a more rapid mortality rate was observed associated with treatment with 100 mg/kg/d in comparison with untreated, infected mice, while animals treated with 4 mg/kg/d of anisomycin died significantly (p