Zika virus (ZIKV) is a major public health concern due to its overwhelming spread into the Americas. Currently there are neither licensed vaccines nor antiviral therapies available for the treatment of ZIKV. We aimed to identify and rationally optimize effective therapeutic regimens for ZIKV by evaluating the antiviral potential of approved broad-spectrum antiviral agents favipiravir (FAV), interferon-alpha (IFN), and ribavirin (RBV) as single agent and combinations. For these studies, Vero cells were infected with ZIKV in the presence of increasing concentrations of FAV, IFN, or/and RBV for four days. Supernatants were harvested daily and viral burden was quantified by plaque assay on Vero cells. The time-course of viral burden during treatment in vitro was characterized by a novel translational, mechanism-based model which was subsequently used to rationally optimize combination dosage regimens. The combination regimen of FAV plus IFN provided the greatest extent of viral inhibition without cytotoxicity, reducing viral burden by 4.4-log10 plaque forming units/ml at concentrations of 250 μM FAV with 100 IU/ml IFN. Importantly, these concentrations are achievable in man. The translational, mechanism-based model yielded unbiased and reasonably precise curve fits. Simulations with the model predicted that clinically relevant regimens of FAV plus IFN would markedly reduce viral burden in man, resulting in at least a 10,000-fold reduction in virus during the first four days of treatment. These findings highlight the substantial promise of rationally optimized FAV plus IFN combination dosage regimens which should be further investigated to combat ZIKV.
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