Abstract
Vector-borne flaviviruses (VBFs) affect human health worldwide, but no approved drugs are available specifically to treat VBF-associated infections. Here, we performed in silico screening of a library of U.S. Food and Drug Administration-approved antiviral drugs for their interaction with Zika virus proteins. Twelve hit drugs were identified by the docking experiments and tested in cell-based antiviral assay systems. Efavirenz, tipranavir, and dasabuvir at micromolar concentrations were identified to inhibit all VBFs tested; i.e., two representatives of mosquito-borne flaviviruses (Zika and West Nile viruses) and one representative of flaviviruses transmitted by ticks (tick-borne encephalitis virus). The results warrant further research into these drugs, either individually or in combination, as possible pan-flavivirus inhibitors.
Highlights
The genus Flavivirus comprises more than 50 members, most of which are transmitted by mosquitoes and ticks [1]
To identify large molecule drugs, we conducted an in silico screen of an Food and Drug Administration (FDA)-approved library for antiviral drugs using Zika virus (ZIKV) protein structures as a Vector-borne flaviviruses (VBFs)-representative model (Table 1)
From the in vitro screening, four antivirals inhibited ZIKV-mediated cytopathic effect (CPE) in cell culture (>90% viability of the infected cells compared to uninfected controls) at a concentration of 50 μM (Figure 2A)
Summary
The genus Flavivirus (family Flaviviridae) comprises more than 50 members, most of which are transmitted by mosquitoes and ticks (vector-borne flaviviruses, VBF) [1]. No approved effective antiviral therapy directed against these viruses is currently available. To address this urgent medical need, we interrogated a library of U.S Food and Drug Administration (FDA)-approved antiviral drugs for the ability to block flavivirus replication in vitro. Such approved drugs have well-documented modes of action, safety, and pharmacokinetic and pharmacodynamic profiles. Identifying them might expedite the regulatory process for their approval in clinical use more rapidly than new compounds [5,6,7,8,9]
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